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Physiol Rev 87: 933963, 2007; doi:10.1152/physrev.00006.2006.
Molecular Physiology of Pituitary Development: Signaling and Transcriptional Networks

XIAOYAN ZHU, ANATOLI S. GLEIBERMAN, AND MICHAEL G. ROSENFELD Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, La Jolla, California
I. Introduction II. Initial Steps of the Anterior Pituitary Development A. Origin of the ectodermal pituitary primordium B. Initial steps of Rathkes pouch development III. Signaling Molecules That Regulate Stratification of Rathkes Pouch and Pituitary Cell Type Determination A. Shh B. FGFs C. BMPs D. Notchs E. Wnts F. EGF IV. Transcriptional Factors That Control the Early Phases of Patterning A. Pitx B. LIM homeodomain transcription factors: Isl1, Lhx3, and Lhx4 C. Hesx1 D. Prop1 E. Six homeodomain transcription factors F. Pax6 V. Corticotrope Differentiation A. Corticotrope lineage specification B. Regulation of POMC expression VI. Differentiation of Pit1 Lineages: Somatotropes, Lactotropes, and Thyrotropes A. Pit1 B. Regulation of Pit1 expression C. Regulation of somatotrope/lactotrope determination D. Regulation of somatotrope-specific gene expression E. Regulation of lactotrope-specific gene expression F. Specification of thyrotrope lineage G. Regulation of GSU gene expression H. Regulation of TSH gene expression VII. Gonadotrope Differentiation A. SF1 and other transcription factors in gonadotrope lineage differentiation and function B. Transcriptional regulation of gonadotrope specific genes VIII. The Hypothalamic/Pituitary Regulatory System A. Sox3 and the morphogenesis of pituitary B. Specification of GHRH neurons: Hmx2/3 and Gsh-1 C. Genetic hierarchy of magnocellular neuron formation: Otp, Sim1/Arnt2, Sim2/Arnt2, and Brn2 D. Specification and migration of GnRH-1 neurons IX. Conclusions
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Zhu X, Gleiberman AS, Rosenfeld MG. Molecular Physiology of Pituitary Development: Signaling and Transcriptional Networks. Physiol Rev 87: 933963, 2007; doi:10.1152/physrev.00006.2006.The pituitary gland is a central endocrine organ regulating basic physiological functions, including growth, the stress response, reproduction, metabolic homeostasis, and lactation. Distinct hormone-producing cell types in the anterior pituitary arise from a common ectodermal primordium during development by extrinsic and intrinsic mechanisms, providing a powerful
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model system for elucidating general principles in mammalian organogenesis. The central purpose of this review is to inspect the integrated signaling and transcriptional events that affect precursor proliferation, cell lineage commitment, terminal differentiation, and physiological regulation by hypothalamic tropic factors.
I. INTRODUCTION The pituitary gland functions as a relay between hypothalamus and peripheral target organs. It is composed of two anatomically and functionally distinct entities, the adenohypophysis, including the anterior and intermediate lobes, and neurohypophysis, also known as the posterior lobe. The adenohypophysis contains six different cell types characterized by different hormones they produce and secrete. Somatotropes secrete growth hormone (GH) and regulate linear growth and metabolism. Lactotropes produce prolactin (PRL), regulating milk production in females. Corticotropes secrete adrenocorticotrophic hormone (ACTH), a proteolytic product of proopiomelanocortin (POMC), which regulates metabolic function through stimulation of glucocorticoid synthesis in the adrenal gland. Thyrotropes produce thyroid-stimulating hormone (TSH), which promotes thyroid follicle development and thyroid hormone (TH) secretion and modulates skeletal remodeling. Gonadotropes produce luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which act on the gonad to initiate sexual maturation and maintain reproductive function. TSH, LH, and FSH are heterodimeric glycoproteins composed of a common -subunit ( GSU) and a hormone-specic -subunit (TSH , LH , FSH ). The intermediate lobe melanotropes secrete melanocyte-stimulating hormone ( -MSH), a cleaved product of POMC, regulating production and distribution of melanin by melanocytes. The posterior lobe of the pituitary is composed of axonal terminals of the magnocellular neurons, surrounded by specialized astroglia known as pituicytes. The magnocellular neurons synthesize peptide hormones oxytocin and vasopressin and transport them to the axonal terminals located in the posterior lobe where they are secreted into the general circulation. The proper function of the pituitary is regulated by the hypothalamus, which secretes trophic factors modulating cell proliferation, hormone synthesis, and secretion (58, 245, 255, 258, 287, 302, 328, 329). II. INITIAL STEPS OF THE ANTERIOR PITUITARY DEVELOPMENT The pituitary gland of all vertebrates is an organ of dual origin. The posterior lobe of the gland derives from neuroectoderm while the anterior and intermediate lobes originate from the so-called hypophysial placode. These two parts of the gland closely interact both physiologically and developmentally. While morphological details as
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well as the organization of the gland vary in different taxa of vertebrates, the general principles of the gland organization, morphogenesis, and molecular machinery involved in the development and functions of terminally differentiated endocrine cell types are quite similar (Fig. 1). A. Origin of the Ectodermal Pituitary Primordium The ectodermal primordium of the anterior pituitary is considered to be a member of cranial placodes (reviewed in Refs. 15, 237). Fate map analysis in amphibians, birds, and mammals traced the origin of the anterior pituitary to the anterior neural ridge, the ectodermal midline structure located immediately anterior to the neural plate (51, 133, 150). The adjacent midline part of the neural plate is destined to become hypothalamus and the posterior lobe of pituitary (neuropituitary) (50). In zebrash as well as in amphibian embryos, the anterior pituitary starts to develop directly from the placode in close contact with the developing neural tissue (91, 135). In birds and mammals, two adjacent areas that are involved in the formation of the pituitary gland are displaced from their anterior position in the process of head morphogenesis. As a result, the pituitary primordium nally ends up as a part of the stomodeal ectoderm at the roof of the oral cavity; concurrently, the presumptive hypothalamus and neuropituitary that still keeps close contact with the hypophysial placode move ventrally and become a part of ventral diencephalon. In birds and mammals, the development of the anterior pituitary per se starts from the formation of the Rathkes pouch, a ngerlike invagination of the roof of oral cavity toward ventral diencephalon. Almost simultaneously, the ventral diencephalon of mammals generates an outgrowth termed infundibulum that is the primordium of the posterior lobe of pituitary. The infundibulum and Rathkes pouch proceed to form a denite pituitary gland. In chick embryo, outgrowth of the infundibulum, as well as further development of the posterior lobe of the pituitary gland, is much less manifested morphologically than in mammals. There are some disputes in the literature regarding neuroectodermal/placodal versus oral ectoderm origin of the anterior pituitary primordium. In a sense, these arguments are purely semantic. Fate map studies clearly indicate a placodal origin of the anterior pituitary in all vertebrates (135). In bird and mammals, transposition of the anterior pituitary primordium into the stomodeal area due to head morphogenesis partially obscures its placodal origin.
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FIG. 1. Ontogeny of signaling molecules and selected transcriptional factors during mouse pituitary organogenesis. The most anterior neural ridge gives rise to primordium of the anterior and intermediate lobes of the pituitary. The adjacent neural plate develops into endocrine hypothalamus and the posterior lobe of the pituitary gland. Ventral diencephalon, which expresses BMP4, FGF8/10/18, and Wnt5, makes direct contact with oral ectoderm and induces the formation of Rathkes pouch. Shh is expressed throughout the oral ectoderm except in the Rathkes pouch, creating a boundary between two ectodermal domains of Shh-expressing and -nonexpressing cells. The opposing dorsal BMP4/FGF and ventral BMP2/Shh gradients convey proliferative and positional cues by regulating combinatorial patterns of transcription factor gene expression. Pit1 is induced at e13.5 in the caudomedial region of the pituitary gland, which ultimately gives rise to somatotropes (S), lactotropes (L), and thyrotropes (T). Rostral tip thyrotropes (Tr) are Pit1 independent. Corticotropes (C) and gonadotropes (G) are differentiated in the most ventral part of the gland. The dorsal region of the Rathkes pouch becomes the intermediate lobe, containing melanotropes (M). The infundibulum grows downward and eventually becomes the posterior lobe (P). A number of transcription factors and cofactors regulating the lineage commitment and terminal differentiation of distinct cell types are illustrated in a genetic pathway. [Modied from Scully and Rosenfeld (255).]
B. Initial Steps of Rathkes Pouch Development The initial step of Rathkes pouch formation as an invagination of the oral ectoderm is apparently dependent on the bone morphogenetic protein (BMP)4, which is expressed in the overlying ventral diencephalon at E8.5 and later in the infundibulum and subsequently diminished. Deletion of BMP4 results in embryonic lethality around gastrulation (E6.5). In some genetic background, however, a proportion of the mutant embryos survive until E9.5. In these mutant animals, the initial ectodermal thickening and the invagination of Rathkes pouch fail to occur (279). However, cautions should be taken given that these mutant animals are consistently developmentally delayed compared with their wild-type littermates (162). It has also been suggested that the initial Rathkes pouch and infundibulum formation as invaginations of oral ectoderm and ventral neuroectoderm, respectively, prePhysiol Rev VOL
cedes their commitment to the pituitary fate and may be induced by morphogenetic signals from prechordal plate/ notochord. Nonspecic Rathkes pouchlike ectodermal invagination can be induced by heterotopic transplantation of prechordal plate/notochord at lateral head ectoderm of early chick embryo (92). This is in agreement with the known ability of notochord-derived signal(s), Shh in particular, to affect adjacent mesenchyme and the composition of extracellular matrix which in turn impacts the migration of placode-derived cells (76). Ectodermal invagination brings primordium of the anterior pituitary in close physical contact with ventral diencephalon. It has been shown that the interaction between these tissues is absolutely essential for further pituitary development (reviewed in Ref. 134). Intriguingly, ventral diencephalon/infundibulum not only promotes further development of Rathkes pouch and terminal differentiation of all endocrine cell types of the anterior
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pituitary (80, 81, 83, 84, 301), but also can induce the differentiation of the anterior pituitary cell types in naive head ectoderm of early chick embryo, such as lateral head ectoderm, presumptive lens, and face ectoderm, as has been demonstrated by in vitro organ culture experiments (78, 79, 92). The process of induction is strictly contactdependent and also requires the presence of mesenchyme. The exact nature of the inducing signal(s) is still unknown. It is unlikely that these signals are identical to growth factor/morphogens responsible for the stratication of the anterior pituitary primordium such as Shh, broblast growth factor (FGF)8 and -10, Bmp2/4, and Wnts factors (see below), as these factors either alone or in combination fail to induce any signs of pituitary differentiation in naive head ectoderm of chick embryo. III. SIGNALING MOLECULES THAT REGULATE STRATIFICATION OF RATHKES POUCH AND PITUITARY CELL TYPE DETERMINATION As in many other organs, patterning of the anterior pituitary primordium is directed by a complex morphogenetic eld that is composed of signals emanating both from ventral diencephalon/infundibulum and from Rathkes pouch itself. The signals that are essential for the stratication of Rathkes pouch and for the timely and spatially organized process of endocrine cell type appearance are the same familiar factors that are involved in the patterning of many other organs, namely, Shh and members of FGF, BMP, Notch, and Wnt families of growth factor/ morphogens (58). The role of epidermal growth factor (EGF) signaling in pituitary development, while quite signicant in the development of somatotrope and lactotrope cell lineages, is much less documented. A. Shh The secreted factor Shh plays an important role in embryo patterning, as well as in the specication of different cell types and in the control of proliferation of numerous cell types. In the early embryo, the major source of Shh production is the notochord (72). Both surgical ablation of notochord in chick embryos and deletion of the Shh gene in mouse result in similar profound changes in the embryo axis patterning and dramatic distortion of head morphogenesis accompanied by malformation of midline structures, cyclopia, and absence of Rathkes pouch (44, 76, 77). Three related zinc nger transcription factors, Gli1, Gli2, and Gli3, acting downstream of the Shh pathway, are expressed in the ventral diencephalon and developing Rathkes pouch (117). Inactivation of Gli2 causes variable loss of the pituitary, and deletion of both Gli1 and Gli2 results in complete abPhysiol Rev VOL
sence of the pituitary (214). The effect on the pituitary development upon ablation of Shh signaling, however, seems to be a consequence of a general defect of midline structures including diencephalon/infundibulum rather than a defect in the anterior pituitary primordium itself. Furthermore, loss of either Shh or the notochord affects dramatically the formation of paired trigeminal ganglia that normally are located laterally to the pituitary gland. In the absence of Shh, a fused single trigeminal ganglion is formed in the place where the pituitary normally develops (76). In zebrash, Shh produced by neuroectoderm instead of notochord or oral ectoderm is crucial for the initial patterning of the pituitary placode (246). Mutations that severely disrupt HH signaling, such as smu/smoothened and yot/Gli2, result in the development of lens tissue from the presumptive pituitary (149). Mutations that attenuate HH signaling, including syu/sonic hedgehog and dtr/Gli1, lead to hypoplasia of the pituitary gland (111, 246). Interestingly, lens tissue differentiation in naive head ectoderm of early chick embryo seems to be the default developmental pathway as opposed to the alternative anterior pituitary formation induced by ventral diencephalons and mesenchyme (16, 78, 79, 92). In mice during pituitary development, Shh is expressed in the ventral diencephalon and oral ectoderm but is excluded from the invaginating Rathkes pouch. The HH downstream target gene Patched1 is expressed in the developing pituitary, indicating that pituitary progenitors respond to the HH signaling. Pituitary-specic blockage of Shh signaling by overexpressing the Shh antagonist Hip almost completely prevents Rathkes pouch growth and appearance of endocrine cell lineages. In contrast, Shh overexpression in the developing pituitary under the control of GSU regulatory element results in mild hyperplasia with expansion of ventral gonadotrope and thyrotrope cell lineages (286). This is consistent with the observation in zebrash where overexpression of shh causes pituitary expansion (246), suggesting that Shh exerts effects on both proliferation and cell type determination. B. FGFs Multiple members of the FGF growth factor family play important roles in every known organogenesis and cell type differentiation, including anterior pituitary. Three members of this family, FGF8, -10, and -18, have been found in the ventral diencephalon and subsequently in the posterior lobe of pituitary during mouse pituitary development (75, 188, 285, 286, 316), and at least two of them, FGF8 and FGF10, have been shown to play important roles in the pituitary development. In mice lacking either FGF10 or the gene encoding its high-afnity receptor, FGF receptor 2 IIIb, the Rathkes pouch initially forms but rapidly undergoes extensive apoptosis resulting in
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agenesis of the anterior pituitary by E14.5 (206, 234). A similar observation has been made in transgenic mice expressing a dominant negative form of FGFR2 (IIIb) (40), suggesting that FGF10 signaling is essential for cell survival. Inactivation of FGF8 in mice causes early lethality at E8.5 before pituitary development. The function of FGF8, which binds to a different set of FGF receptors, in pituitary development, is largely drawn from studies of transgenic animals and in vitro organ culture. Overexpression of FGF8 under the control of GSU regulatory element leads to ectopic Lhx3 induction and pituitary hyperplasia with dramatic expansion of POMC-producing cell lineages and simultaneous inhibition of other pituitary cell types (285, 286). When cocultured in vitro, the infundibulum can stimulate proliferation and induce Lhx3 expression, meanwhile antagonizing BMP2-induced expression of Isl1, GSU in Rathkes pouch explants. The patterning activity of the infundibulum can be mimicked at least in part by FGF8, and impeded by the FGF receptor antagonist SU5402, suggesting that FGF8 is an important component of signals emanated from ventral diencephalon. It functions in the patterning of Rathkes pouch by maintaining proliferation and opposing the ventral BMP2 differentiation signal (75, 203). The function of FGF signaling in pituitary development has previously been implicated in mice lacking Titf1, where the entire pituitary is completely absent at birth. Titf1 is expressed in the ventral diencephalon. In Titf1 / mice, the region that expresses FGF8 and FGF10 is deleted leading to a failure of Lhx3 and Lhx4 induction. The initial oral ectoderm invagination is ultimately eliminated by apoptosis (145, 279). In zebrash, it has also been found that Fgf3, a ligand for FGFR2 (IIIb), is required for activation of genes regulating early steps of pituitary specication, including lim3/ Lhx3 and pit1, and is essential for subsequent cell survival. Mutations in Fgf3 or blocking FGF signaling by the FGFR inhibitor SU5402, however, affect neither pituitary morphogenesis nor pituitary cell proliferation (110). Fgf3 is also required for pituitary-specic expression of ascl1a, which encodes a homolog of basic helix-loop-helix (bHLH) proteins of the achaete-scute subfamily. Similar to Fgf3/lia mutants, ascl1a/pia mutants exhibit a failure of terminal differentiation of all pituitary cell types, lacking expression of pit1 and neurod. Interestingly, implanted Fgf3 beads can enhance pituitary ascl1a expression but fail to rescue pit1 expression and pituitary development defects of ascl1a/pia mutants, suggesting that ascl1a might act in parallel or downstream of Fgf3 signaling to mediate some effects of Fgf3 (219). C. BMPs BMP signaling is crucial for the anterior pituitary development. At least two members of the BMP family,
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BMP4 and BMP2, participate in the development of the anterior pituitary. As noted above, BMP4 is suggested to be essential for the invagination of Rathkes pouch (279). Consistently, oral ectoderm invagination occurs in Titf1 / mice, wherein expression domain of BMP4 is maintained at E9.5 despite lacking FGF8 and FGF10. Similarly, in transgenic mice intended to block early BMP signaling by overexpressing Noggin, a high-afnity BMP2/4 antagonist, in the oral ectoderm and Rathkes pouch under the control of Pitx1 regulatory sequences, pituitary development is arrested at E10 after the pouch formation lacking all pituitary cell types except for a few corticotropes (285), suggesting that BMP4 signaling is critical for the continued progression of pituitary development. The pituitary phenotype of Pitx1-Noggin transgenic mice is almost identical to that of the Lhx3 / mice (259). It remains to be determined whether BMP4, like FGF8, also regulates the expression or functions of Lhx3. Subsequent to the onset expression of BMP4 in ventral diencephalon, BMP2 signal emanates from a ventral part of the anterior pituitary primordium at E10.5. In vitro culture of Rathkes pouch in the presence of BMP2 has shown that BMP2 is capable of inducing the expression of Isl1 and GSU, both of which are ventral markers of pituitary, and suppressing the expression of ACTH. Moreover, overexpression of BMP4 in the developing pituitary under the pituitary-specic promoter GSU leads to mild hyperplasia of the anterior pituitary with overgrowth of ventral cell types as judged by their transcription factor prole. These data collectively suggest that BMP2 signaling provides a ventralizing positional cue for pituitary development (75, 285). This BMP2 signal together with a dorsal FGF8 signal appear to create opposing gradients that are suggested to generate temporally and spatially distinct patterns of transcription factors expression underlying cell lineage specication events (58, 75, 285). Interestingly, while BMP signaling is absolutely essential for the initiation of the cell type determination process, it has to be attenuated to achieve terminal differentiation. Normally, during anterior pituitary development the expression of BMP2 decreases dramatically after E14 15. Overriding this decline by sustained expression of BMP4 in GSU-BMP4 transgenic mice leads to a failure of terminal differentiation as evidenced by lack of any terminal differentiation markers (285). D. Notchs Notch signaling is an evolutionally conserved mechanism that regulates proliferation, apoptosis, cell fate determination, and morphogenesis. Notch signaling is active during the early phases of pituitary development as indicated by expression of Dll1, Jag1, Notch2, Notch3, as well as the direct downstream targets Hes1 and Hey1. Their
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expression becomes downregulated in the perspective anterior pituitary at E13.5 as cells undergo lineage commitment (226, 228, 330). Pituitary-specic inactivation of Rbp-J, which encodes a central mediator of the Notch signaling, using the transgenic Cre line under the control of Pitx1 regulatory sequences, leads to premature differentiation of progenitor cells as well as a conversion of the Pit1 lineage into corticotrope lineage. The former phenotype is recapitulated in mice deleted for the Hes1 gene, while the later phenotype is largely attributed to the signicant downregulation of Prop1 at E12.5, which encodes the tissue-specic paired-like homeodomain transcription factor necessary for Pit1 expression. It has been shown that Rbp-J can bind to the evolutionally conserved recognition site in the rst intron of the Prop1 gene and is recruited to this region during pituitary development, suggesting that Notch signaling directly regulates Prop1 transcription and is required for maintaining high-level expression of Prop1. These data collectively demonstrate that Notch signaling is required for generating diverse precursor pools and suggest that duration/intensity of Notch activity plays a critical role in lineage commitment (330). In the later phases of pituitary development, Notch activity is dramatically attenuated, which is absolutely required for terminal differentiation of distinct cell lineages (228, 330). Overexpression of the constitutively active form of Notch1 in Pit1 cells under the control of Pit1 regulatory information (Pit1-NICD) completely blocks terminal differentiation of all three Pit1 lineages. Consistently, overexpression of the constitutively active form of Notch2 in thyrotropes and gonadotropes directed by the GSU regulatory sequences leads to defects in thyrotrope and gonadotrope differentiation. Other components of the Notch pathway, including a subset of Notch-repressed neurogenic bHLH factors Mash1 and Math3, are expressed during pituitary development. It has also been shown that Mash1 and Math3 play critical roles in differentiation and functions of specic cell types (330; unpublished data). E. Wnts Wnt signaling plays an important role in the control of proliferation of many cell types as well as in the patterning and in the maintenance of stem cell fate. During pituitary development, the Wnt/ -catenin pathway is active between E11.5 and E15.5, as indicated by expression of a direct downstream target Axin2, and is functionally required for Pit1 lineage determination and pituitary gland growth. Targeted inactivation of the -catenin gene in pituitary progenitors using the Pitx1-Cre transgenic line results in a smaller gland with no Pit1 expression, absence of three Pit1 lineages, and reduced number of gonadotropes. Unlike in most other developmental proPhysiol Rev VOL
cesses regulated by the canonical Wnt pathway where Wnt signaling is conveyed by association of -catenin with the Lef/Tcf family of transcription factors, induction of Pit1 expression is mediated by direct interactions between -catenin and the tissue-specic paired-like homeodomain transcription factor Prop1, through an evolutionarily conserved Pit1 early enhancer (66, 208, 273). The Prop1/ -catenin complex also acts as a transcriptional repressor for Hesx1, based on the recruitment of Groucho-related Tle, histone deacetylase (HDAC), and Reptin corepressors. Genetic studies have demonstrated that temporal control of the Wnt/ -catenin signaling is essential for proper pituitary development as premature activation of -catenin leads to Hesx1 repression and pituitary gland agenesis by E13.5 (208). Ten of 19 Wnt genes are detected in the developing E12.5 pituitary (208). So far, two of them, Wnt4 and Wnt5a, have been reported to be specically associated with the developmental events in the anterior pituitary. Wnt5a is expressed in the ventral diencephalon and infundibulum of mouse embryo since at least E9.5, while Wnt4 expression is detected in Rathkes pouch and sustained later through E14.5 (285). Surprisingly, ablation of either gene results in relatively mild phenotype in the developing anterior pituitary. Wnt4 / mice have anterior pituitary hypoplasia with reduced number of gonadotropes, thyrotropes, and somatotropes, but not corticotropes (285). Wnt5a / mice have morphologically distorted pituitary with enlarged intermediate lobe and increased number of POMC in the anterior and intermediate lobes (41; unpublished observations). The double Wnt4/Wnt5a knockout mice display a combined phenotype with signicantly abnormal shape of pituitary gland, hyperplasia of the intermediate lobe, and hypoplasia of the anterior lobe accompanied by an increased number of corticotropes and decreased number of all other endocrine cell types (unpublished observations). It seems that these two factors target independent, discrete, nonoverlapping populations of pituitary precursors, and they play a role not in the specication of particular cell lineages but rather in the expansion of endocrine cell types. Whether other members of the Wnt family in combination with Wnt4, -5a play a role in lineage specication, as implicated by the pituitary specic deletion of the -catenin gene, awaits further investigation. Other components of the Wnt/ -catenin signaling pathway, including frizzled2 (Fzd2), Lef1, Tcf3, and Tcf4, are expressed during pituitary development (69, 208). Fzd2 is detectable in Rathkes pouch and infundibulum at E12.5 (69). Tcf3 is expressed from E9.0 to E14.5 but is restricted from the Pit1-expressing caudomedial region of the gland. Tcf4 is detectable in early pituitary as well as in surrounding tissues and is markedly diminished by E13.5. Lef1 exhibits biphasic expression, initial transiently at E9.0 in Rathkes pouch and later reappearing at
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E13.5 in anterior and intermediate lobes of the gland (208). Targeted inactivation of Tcf4 results in hyperplasia of the anterior lobe without affecting other aspects of pituitary development (30). Deletion of Lef1, on the other hand, leads to elevated expression of Pit1 as well as GH and TSH , consistent with a role of Lef1 in inhibiting Prop1/ -catenin-mediated Pit1 activation (208). F. EGF While EGF signaling plays a very important role in many developmental processes, its role in the development of pituitary gland has not been studied in detail. Recently, it has been found that blocking EGF/transforming growth factor (TGF)- signaling, by the expression of a dominant-negative form of EGF receptor lacking its intracellular protein kinase domain, has a profound stagespecic effect (240). Expression of mutated EGF receptor in GH-producing cells of embryonic pituitary results in dwarsm and pituitary hypoplasia with reduced numbers of both somatotropes and lactotropes. Delaying mutated receptor expression in somatotropes to the postnatal period or targeting its expression to lactotropes does not cause any discernable phenotype. These data demonstrate an essential role of EGF or TGF- signaling in the early steps of development of somatotrope/lactotrope cell lineages. Whether this pathway is involved in any other developmental events in the pituitary gland remains to be addressed. IV. TRANSCRIPTIONAL FACTORS THAT CONTROL THE EARLY PHASES OF PATTERNING A. Pitx Three bicoid-related Pitx transcription factors have been identied. Two of them, Pitx1 and Pitx2, exhibit overlapping and distinct expression patterns during pituitary development (reviewed in Ref. 89). Both transcription factors can recognize the same bicoid binding site and activate the promoters of multiple pituitary hormones including GSU, TSH , LH , FSH , GnRHR, PRL, and GH (289). Genetic studies have demonstrated that they are required for cell proliferation, survival, and differentiation in a dosage-sensitive manner, with Pitx2 playing a more prominent role than Pitx1, and they function redundantly in controlling Lhx3 expression (43, 146, 274). Pitx1 was identied on the basis of its ability to interact with the NH2-terminal transactivation domain of Pit1 (278) and to bind a cis-acting element of the POMC promoter (159). Inactivation of Pitx1 results in defects in hindlimb development and craniofacial morphogenesis (160, 277). The
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anterior pituitaries of Pitx1 / mice exhibit mild defects with decreased expression of FSH , LH , and TSH and increased expression of POMC. The Pitx2 gene was initially identied as the gene responsible for human Rieger syndrome type I, an autosomal dominant condition characterized by variable defects including anomalies of anterior chamber of the eye, dental hypoplasia, a protuberant umbilicus, mental retardation, and isolated growth hormone deciency (256). Pitx2 knockout mice display multiple developmental defects including failure of body-wall closure, right pulmonary isomerism, and defects in heart, tooth, eye, and pituitary organogenesis (88, 148, 170, 181). In the pituitary, a denite pouch forms with induction of Lhx3, Hesx1, Pitx1, and GSU. However, the gland fails to progress further with only a few POMC-positive corticotropes and no Pit1 induction. Decreased proliferation or reduced gland size has been observed in the pituitaries of Pitx2 / , Pitx1 / Pitx2 / and Pitx1 / Pitx2neo/neo (a hypomorphic allele of Pitx2) embryos, suggesting that Pitx1 and Pitx2 function in the same pathway to stimulate cell proliferation. Consistent with this view, overexpression of Pitx2 under the control of Pit1 or GSU regulatory elements leads to an increase in the number of somatotropes and gonadotropes, respectively (43, 146, 274). Cell culture studies also show that the Wnt/ -catenin pathway can stimulate expression of Pitx2, which in turn regulates expression and mRNA stability of critical cell cycle regulators including Cyclin D1, D2 (13, 27, 146). It has also been demonstrated that Pitx2 is required for cell survival, and Pitx1 and Pitx2 together are obligatory for Lhx3 induction (43). In addition to the early roles of Pitx2 in pituitary development, studies of Pitx2neo/neo mice reveal that Pitx2 is necessary for expansion of the Pit1 lineages and differentiation of gonadotropes at later stages of pituitary organogenesis (274). The requirement of Pitx1 and Pitx2 for terminal differentiation in the ventral cell types maybe explained, at least in part by the fact that both Pitx1 and Pitx2 are preferentially expressed in these cells (43). B. LIM Homeodomain Transcription Factors: Isl1, Lhx3, and Lhx4 LIM homeodomain proteins (LIM-HD) are characterized by two tandemly repeated LIM domains located NH2terminally of the DNA binding homeodomain. The LIM domain provides a protein-protein interaction interface that recruits cofactors mediating LIM-HD functions (reviewed in Ref. 118). At least 12 members of the LIM-HD family have been identied in mammals, and several of them are expressed in Rathkes pouch, including Isl1, Lhx3, and Lhx4. Expression of Isl1 in pituitary is dynamic. It is initially detected in the oral ectoderm at E8.5,
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throughout Rathkes pouch at E9.5, and then by E10.5 conned to the most ventral region of the pouch, apparently colocalized with GSU in the rostral tip thyrotropes. Isl1 expression is induced by BMP2 and repressed by FGF8/FGF2, the opposing ventral and dorsal signals critical for pituitary development (75). Inactivation of Isl1 results in embryonic lethality at approximately E10 with defects in heart, pancreas, and motor neuron development. In E9.5 Isl1 / embryos, the primitive pouch forms with aberrant thin epithelium, suggesting that Isl1 is necessary for proliferation and differentiation of pituitary progenitors (279). Similar functions of Isl1 have been elucidated in heart development, where Isl1 is expressed in precursors of the second heart eld and essential for their proliferation, survival, and migration (34). Lhx3 is expressed in the pituitary gland, motor neurons of the spinal cord and hindbrain, the retina, and the pineal gland. Lhx3 expression is rst evident in Rathkes pouch at E9.5 and persists predominantly in the anterior and intermediate lobes of the adult pituitary. Mice with disrupted Lhx3 are stillborn or die within 24 h lacking the anterior and intermediate lobes of the pituitary. In Lhx3 / mice, the pituitary gland is arrested after the formation of a denite Rathkes pouch with a failure to maintain Hesx1 expression and to induce Pit1. Except for some residual corticotropes, all other cell types in the anterior and intermediate lobes are completely absent (259). A more extensive analysis of the Lhx3Cre/Cre mutants, which carry a Cre recombinase expressing cassette in the 3 -UTR of the Lhx3 gene leading to reduced expression of Lhx3 protein and pituitary defects identical to those in Lhx3 / mutants, reveal that Lhx3 is required for cell survival, consistent with the view that Lhx3 acts downstream of Pitx1 and Pitx2 in preventing cell apoptosis (326). The function of LHX3 is conserved in humans. Patients with loss-of-function mutations in LHX3 have combined pituitary hormone deciency (CPHD) (reviewed in Refs. 21, 46, 53, 193). Because disruption of either Lhx3 or Isl1 results in an arrest of pituitary development at early stages, their functions in the later stages cannot be determined by analyzing the mutant mice. In vitro studies have shown that Lhx3 can interact with other transcription factors found in pituitary and synergistically regulate the promoters of pituitary hormones and transcription factor genes. For example, Lhx3 with Pitx1 synergistically activates the promoter of GSU and with Pit1 regulates the promoter of PRL, Pit1 and TSH (11, 271). A closed related gene, Lhx4, is also expressed in the invaginating pouch at E9.5. In contrast to Lhx3 that is expressed throughout adulthood, Lhx4 expression becomes restricted to the future anterior lobe of pituitary and diminished at E15.5. Mice homozygous for the Lhx4 deletion die shortly after birth due to a failure of pulmonary maturation. In Lhx4 / mice, there is increased cell
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death in E12.5 and E14.5 pituitary, and by E18.5 different cell types, including somatotropes, corticotropes, thyrotropes, and gonadotropes, are present, but with markedly reduced numbers leading to a hypoplastic anterior lobe. In addition to distinct roles of Lhx3 and Lhx4 in pituitary organogenesis, Lhx3 and Lhx4 act redundantly in the formation of a denitive pouch. Inactivation of both Lhx3 and Lhx4 results in a more severe phenotype than either single mutant with an earlier developmental arrest in pituitary (227, 257). C. Hesx1 Hesx1 is a member of the paired-like class of homeodomain genes. It is rst expressed in the anterior midline endoderm and prechordal plate precursor, subsequently activated in the overlying ectoderm of the cephalic neural plate, and ultimately restricted to the ventral diencephalon and Rathkes pouch at E9.5 (108, 109, 280). Expression in the developing pituitary persists until E12, when Hesx1 is downregulated in a spatial and temporal order that coincides with the rise of Prop1 transcripts and progressive differentiation of pituitary specic cell types. Hesx1 expression is regulated by Lhx3 and Prop1. While Lhx3 is necessary to maintain Hesx1 expression, Prop1/ -catenin is required for Hesx1 repression (208, 259, 273). Inactivation of Hesx1 results in variable anterior central nervous system (CNS) defects, including a reduced prosencephalon, absence of developing optic vesicles, and defective olfactory development (59, 187). The phenotypes in the pituitary diverge greatly. Five percent of Hesx1 / embryos exhibit a complete lack of pituitary gland. The initial thickening of oral ectoderm and minimal induction of Lhx3 occur at E12.5; the pituitary gland however is absent at E18.5, probably owing to ectopic expression of FGF8 in the oral ectoderm. The majority of Hesx1 / mice are characterized by multiple oral ectoderm invagination and/or overproliferation of all pituitary cell types. In these mutants, the expression domain of FGF10 extends rostrally in the ventral diencephalon, leading to ectopic Lhx3 induction and formation of multiple pituitary glands, consistent with the role of FGF signaling in pituitary proliferation and development (56, 75, 206, 233, 285). The phenotype of Hesx1 / mice is similar to that of septo-optic dysplasia (SOD) in human, which is characterized by midline forebrain abnormalities, optic nerve hypoplasia, and hypopituitarism ranging from CPHD to isolated growth hormone deciency (IGHD) (reviewed in Refs. 46, 53, 193, 328). Hesx1 is a transcriptional repressor with two repressor domains located in the NH2-terminal and homeodomain regions, respectively (28, 56). The homeodomain recruits the NcoR/Sin3/HDAC corepressor complex. The NH2 terminus eh1 motif mediates the interaction with the
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Groucho-related Tle corepressor, and their association is essential for Hesx1 function. Tle1 exhibits similar temporal and spatial patterns of expression to Hesx1 in Rathkes pouch. Overproduction of both Hesx1 and Tle1, but not the mutant Hesx1 incapable of interacting with Tle1, in Rathkes pouch results in near-complete absence of gonadotropes and three Pit1 lineages, probably by antagonizing the transactivation function of Prop1 on endogenous targets, suggesting that the interaction between Hesx1 and Tle is required for Hesx1 function and the temporal regulation of Hesx1/Tle complex is fundamental for pituitary organogenesis (56, 273). Recent identication of a homozygous mutation in the eh1 motif of human HESX1 in a patient with CPHD has further underlined that Tle association is an integral mechanism for Hesx1 function in vivo (38). In addition to Tle1, other members of the Tle family, including Tle3, Tle4, and Aes, are expressed during pituitary development. Tle3 is rst detectable in the ventral diencephalon, and by E14.5, Tle3 is localized in the dorsal region of Rathkes pouch and later conned to the intermediate lobe. Tle4 is expressed in the developing infundibulum and posterior lobe and diminished by E16.5. Aes is transiently expressed in the dorsal region of Rathkes pouch from E12.5 to E16.5. While the endogenous functions of Tle1, Tle3, and Tle4 during pituitary development are currently unknown, it has been shown that Aes is required for modeling the shape of pituitary gland. Inactivation of Aes leads to bifurcations of the pouch and severe pituitary dysmorphogenesis at birth (30). D. Prop1 Prop1 is a paired-like homeodomain transcription factor essential for pituitary development and function. Prop1 can bind to its cognate site and activate target gene via the COOH-terminal transactivation domain, whereas the NH2 terminus and the homeodomain of Prop1 possess repression function (266, 273), suggesting that Prop1 can function as both a transcriptional activator and a repressor. Consistent with this notion, recent studies of the pituitary specic inactivation of the -catenin gene reveal that Prop1/ -catenin complex acts as a transcriptional activator for Pit1 and a transcriptional repressor for Hesx1, depending on the associated cofactors (208). Expression of Prop1 is restricted in the developing pituitary. It is initially detected at E10 to E10.5, peaks at E12.5, and declines after E14.5. It has been shown recently that the Notch signaling is required for maintaining high levels of Prop1 expression at E12.5, a process mediated by an evolutionarily conserved Rbp-J binding site within the rst intron of the Prop1 gene (330). A homozygous mutation in the Prop1 homeodomain in the Ames dwarf mice (df/df) or targeted deletion of the Prop1 gene leads to a
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failure of Pit1 gene activation and delayed gonadotrope development. Proliferation of the pituitary progenitors surrounding the lumen is not affected. However, they fail to migrate to the caudomedial region of the developing gland where Pit1 is normally expressed, resulting in an expansion of luminal structure and dramatic dysmorphogenesis (8, 86, 87, 199, 208, 273, 299). Enhanced apoptosis is evident in the postnatal pituitaries of df/df mice, leading to a hypoplastic anterior pituitary (299). In addition to Pit1, both Wnt pathway and Notch pathway are apparently affected in the Ames mice (69, 226). Human PROP1 possesses similar function in pituitary development. Mutations in PROP1 are the leading cause of CPHD in humans (46, 53, 193, 315). Genetic studies have demonstrated that temporal regulation of Prop1 expression is critical for proper pituitary development. Premature expression of Prop1 in Rathkes pouch proves to be deleterious leading to agenesis of the anterior pituitary gland probably by inhibiting the endogenous function of Hesx1 (56). In contrast, persistent expression of Prop1 in thyrotropes and gonadotropes under the control of GSU element delays gonadotrope differentiation and leads to transient hypogonadotropic hypogonadism and increased susceptibility to pituitary adenomas (54, 295). E. Six Homeodomain Transcription Factors Six genes are mammalian homologs of Drosophila melanogaster sine oculis (so) homeobox containing genes. Studies in Drosophila and mammalian systems reveal that an interactive network of the regulatory genes comprising eyeless (ey)/Pax6, so/Six, eyes absent (eya)/ Eya, and dachshund (dach)/Dach is required for the eye patterning (reviewed in Refs. 132, 268, 304). In mammals, six members of the Six family have been identied, which belong to three subfamilies based on sequence conservation: (so) Six1, 2; (six4) Six4, 5; (optix) Six3, 6. Four of the Six genes, Six1, Six3, Six4, and Six6, are expressed in the developing pituitary. Six1 and Six4 are coexpressed in many embryonic primordium structures including Rathkes pouch (reviewed in Ref. 132). Six1 is required for the development of many organs and plays an important role in regulating cell proliferation. Loss of Six1 results in defects in most of the organs where Six1 is expressed, whereas inactivation of Six4 does not cause any embryonic defects (47, 154, 155, 167, 210, 211, 320, 327, 331). However, pituitary development is not affected in either Six1 / or Six4 / embryos. A recent screen for target genes of Six1 and Six4, respectively, reveal that they regulate overlapping and distinct sets of genes, implying that Six1 and Six4 may share overlapping functions (10). Indeed, inactivation of both Six1 and Six4 leads to more severe phenotypes than either single mutant with
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craniofacial and rib defects and general muscle hypoplasia (99). Further analysis of Six1 / Six4 / will facilitate our understanding of the roles of Six1/4 in the process of pituitary organogenesis. Six1 regulates transcription of its target genes by recruiting cofactors via the Six domain. Six1 can either function as a repressor by interaction with Dach or Tle family members, or as an activator by interaction with Eya proteins. Eya family proteins are characterized by a highly conserved COOH-terminal region known as the Eya domain, which mediates interactions with Six and Dach, as well as the less conserved NH2-terminal transactivation domain (31, 106, 167, 205, 267, 319). Recently, three laboratories have independently demonstrated that Eya domains possess intrinsic phosphatase activity that is required for Eya proteins function (167, 229, 283; reviewed in Ref. 230). Six1 and Eya1 exhibit genetic interactions in regulating organogenesis. Loss of Eya1 leads to phenotypes resembling those of Six1 / mice in renal and otic development with abnormal apoptosis of organ primordia; pituitary development is nonetheless not affected (167, 318, 331). However, in Six1 / Eya1 / embryos, the pituitary gland is 5- to 10-fold smaller than the wild-type gland, suggesting that Six1 and Eya1 cooperate to regulate pituitary development. In zebrash, six1 and eya1 are coexpressed in all pituitary cell types. While consistent with ndings in other systems, six1 plays a role in modulating proliferation of pituitary cells; eya1 is required for lineage-specic differentiation. All the cell lineages except lactotropes are affected in eya1 mutants. Differentiation of corticotropes, melanotropes, and gonadotropes is completely impaired, whereas differentiation of somatotropes and thyrotropes initiates; expression of cognate hormone genes gh and tsh , however, fails to be maintained probably due to progressive loss of pit1 expression. Unlike in other systems or organs, eya1 is not required for the survival of pituitary cells, thereby uncoupling the differentiation-promoting and antiapoptotic functions of Eya proteins (202). Six6 expression in pituitary exhibits a dorsal-ventral gradient at the early stage of pituitary development. At E13.5, the expression declines in the differentiated cells while persistent in periluminal cells. Deletion of Six6 results in hypoplastic pituitary and retina with reduced number of terminal differentiated cells due to defects in precursor cell proliferation. In retina, Six6 directly represses expression of p27Kip1 by recruiting corepressor complexes (168). Six3 is expressed in the most anterior part of the developing neural plate and later is restricted in retina precursor cells and pituitary. Six3 promotes cell proliferation and counteracts Wnt and BMP signalings and therefore specifying anterior identity (90, 156). Because of anterior patterning defects associated with loss of Six3, the specic requirement of Six3 in pituitary development remains to be determined. Intriguingly, Six3
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can also promote proliferation by sequestering Geminin from Cdt1, the key component for the assembly of the prereplication complex (64, 182). F. Pax6 Pax6 is a highly conserved member of a family of transcription factors containing a paired domain and a homeodomain. Studies of the mice carrying mutations in the Pax6 gene and Pax6-deleted mice have established that Pax6 is required for the development of the eye, olfactory system, brain, spinal cord, and pancreas. Pax6 is initially expressed in the anterior neural plate that will become telencephalon, diencephalon, eyes, and pituitary. During pituitary development, Pax6 is expressed in the oral ectoderm at E9.0, but is excluded from the Shh expressing region. By E10-E12, Pax6 expression is detected in the Rathkes pouch with an apparent dorsal/ ventral gradient and becomes downregulated at E13.5 and diminished when cells reach terminal differentiation at E17.5. Pax6 deciency leads to a dorsal expansion of ventral GSU-expressing cell types, predominately thyrotropes, at the expense of dorsal cell types somatotropes and lactotropes. Thus the transient expression of Pax6 is required to establish the boundary between dorsal somatotropes/lactotropes and ventral thyrotropes/gonadotropes territories (19, 147). The similar scheme of Pax6 in the dorsal/ventral patterning and specication of cell types is reiterated in CNS forebrain and spinal cord development (reviewed in Ref. 270). V. CORTICOTROPE DIFFERENTIATION A. Corticotrope Lineage Specication ACTH-producing corticotrope is the rst pituitary cell type to reach terminal differentiation. The POMCexpressing corticotropes occur at E12.5 followed by TSHpositive thyrotropes at E14.5, GH-positive somatotropes at E15.5, PRL-positive lactotropes at E16.5, and nally FSH and LH expression gonadotropes around E16.5 (124, 269). With the use of transgenic mice, it has been demonstrated that the 480-bp POMC promoter is sufcient to target expression in developing pituitary (103, 174, 291), whereas the distal enhancer region ( 13 to 9 kb) is required for expression in ventral diencephalon (63). Analyses of regulatory elements in the POMC promoter, using transgenic mice or the corticotrope cell line AtT20 as a model system, have revealed the binding sites for bHLH proteins, orphan nuclear receptors Nur, Pitx factors, and T-box factors (158, 159, 175, 185, 217, 218). The zebrash POMC gene promoter 451 to 61, containing similar regulatory elements, can target expression in corwww.prv.org
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ticotropes, suggesting a conserved mechanism to regulate corticotrope differentiation (179). NeuroD1 is a class B bHLH transcription factor. It is expressed in pancreatic endocrine cells, the intestine, developing CNS, and pituitary. In pituitary, NeuroD1 protein is detectable between E12 and E15.5. It has been shown that NeuroD1/E47 heterodimer can bind to an E-box in the promoter of POMC and activate transcription either alone or in synergy with Pitx1 and Tbx19 through direct interactions of E47/Pitx1 and E47/Tbx19 (157, 220, 221). Human and mice with NeuroD1 deciency develop diabetes due to a failure to develop mature islets (200). Corticotrope differentiation is transiently delayed in NeuroD1 / and NeuroD1 / mice in a dosage-sensitive manner. However, corticotrope lineage commitment, indicated by Tbx19 expression, is not affected in the absence of NeuroD1, suggesting that NeuroD1 is required for the appropriate timing of corticotrope terminal differentiation (157, 176). Whether other members of bHLH family can function redundantly with NeuroD1 to control lineage commitment remains to be determined (176). Tbx19, also known as Tpit, is a member of T-box transcription factors with a characteristic 180-amino acid DNA binding domain that plays a critical role in embryonic development (reviewed in Ref. 197). Mouse Tbx19 was identied in a screen for genes encoding T-box binding proteins present in POMC expressing AtT20 cells (158). It was also cloned as a homolog of the human TBX19 gene (176). Tbx19 expression is initiated at E11.5 in the most caudoventral region of the Rathkes pouch before the onset of POMC expression. Tbx19 is also expressed in the ventral diencephalon, although wherein no protein is detected. In the pituitary, Tbx19 is restricted in the two POMC-expressing lineages, anterior lobe corticotropes and intermediate lobe melanotropes (158, 176). Tbx19 recognizes a T-box element located next to the Pitx1 binding site in the POMC promoter and synergizes with Pitx1 in activating the POMC promoter by recruiting SRC/p160 coactivators (158, 176, 184). The function of Tbx19 has been revealed by both loss-of-function and gain-of-function studies. Inactivation of Tbx19 leads to a failure of corticotrope and melanotrope terminal differentiation, although early corticotrope lineage commitment seems to be intact as indicated by NeuroD1 expression. Tbx19 is also required in POMC-expressing cells to repress alternate cell fates. In the absence of Tbx19, the intermediate lobe is hypoplastic with almost complete loss of the POMC-expressing melanotropes. The presumptive melanotropes as well as corticotropes in the ventrocaudal region of the anterior pituitary instead adopt cell fates of gonadotrope and Pit1-independent rostral tip thyrotrope (223). In contrast, overexpression of Tbx19 under the control of GSU regulatory sequences results in ectopic activation of ACTH in the rostral tip and marked reduction of GSU, TSH , LH , FSH , and SF1 expresPhysiol Rev VOL
sion in thyrotropes and/or gonadotropes (158, 176, 223). Thus Tbx19 promotes terminal differentiation of corticotropes and melanotropes by stimulating POMC expression and preventing differentiation of alternative cell fates (136, 223). Consistent with this notion, Tbx19 can antagonize Lhx3 and Pitx1 on the GSU promoter and SF1 on an SF1-responsive promoter (176, 223). Interestingly, NeuroD1 is not expressed in the ectopically induced corticotropes in Tbx19 transgenic mice, implying that NeuroD1 is not obligatory for corticotrope differentiation and Tbx19 functions independent of NeuroD1 (158). Tbx19 / mice have low plasma ACTH levels and impaired adrenal function (222). Similarly, mutations in human TBX19 gene are the leading cause for neonatal-onset isolated ACTH deciency (222, 293).
B. Regulation of POMC Expression The major role of corticotropes is their ability to respond rapidly to a variety of stress and inammation stimuli. The POMC promoter is positively regulated by hypothalamic hormone corticotropin-releasing-hormone (CRH) through rapid and transient activation and induction of the three Nur subfamily transcription factors, including Nur77, Nurr1, and NOR1. Two Nur binding sites have been identied in the POMC promoter, the distal Nur response element (NurRE), which can be recognized by either homo- or heterodimers formed between subfamily members, and proximal monomer Nur77-binding response element (NBRE). However, only the NurRE site is necessary for CRH responsiveness in AtT20 cells. Additionally, a dominant negative mutant of Nur77 blocks the action of CRH on the POMC promoter, suggesting that the Nur factors are the major integrator of the CRH signal in pituitary corticotropes (185, 218). CRH stimulation activates Nur factors through the protein kinase A (PKA) pathway by increasing the DNA binding activity of Nur77 dimers and enhancing recruitment of p160/SRC transcription coactivators via the AF-1 domain of Nur77 (184). ACTH regulates metabolic functions through stimulation of glucocorticoid synthesis in the adrenal gland. Glucocorticoids in turn mediate the feedback repression of the POMC expression by interaction with the glucocorticoid receptor (GR). Consistent with this notion, in GR / mice where the negative feedback is disrupted, there is a marked increase in POMC expression in corticotropes (232). DNA binding of GR is required for repression of the POMC gene in vivo as demonstrated in the mice carrying a point mutation in the dimerization domain of GR (GRdim, Ala458Thr) (231). In AtT20 corticotropes, glucocorticoids antagonize the actions of CRH by transrepression involving Swi/Snf chromatin remodeling protein Brg1-mediated recruitment of GR and coreprerssor HDAC2 to the Nur77-bound NurRE site (22, 186). Loss of
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nuclear expression of Brg1 or HDAC2 is associated with 50% glucocorticoid-resistant human and dog corticotrope adenomas (22). Leukemia inhibitory factor (LIF) is a pleiotropic neuroimmune cytokine that promotes corticotrope differentiation and induces POMC expression and ACTH secretion. The role of LIF in corticotrope differentiation has been demonstrated by gain-of-function studies. Transgenic mice expressing LIF in somatotropes exhibit striking dwarsm with decreased number of somatotropes and lactotropes and increased number of corticotropes. Overexpressing LIF early during pituitary development under the control of GSU regulatory sequences leads to a signicant expansion of corticotropes and a dramatic decrease of somatotropes, lactotropes, and gonadotropes as well as a variably diminished thyrotropes. Lhx3 and Pit1 expression are decreased at E14.5 in transgenic mice. Thus LIF may repress Lhx3-dependent cell fates (somatotropes, lactotropes, thyrotropes, and gonadotropes) and drive pituitary progenitors differentiation toward corticotrope lineage (4, 321). In contrast, inactivation of LIFR results in a 30% decrease in pituitary POMC mRNA levels, consistent with the idea that LIF regulates POMC expression (300). LIF stimulates POMC expression by activating the JAK/STAT pathway. Two regions in the POMC promoter are responsive to LIF induction. A distal region harbors a STAT binding site, whereas a proximal site does not display STAT binding activity and may thus involve a DNA binding-independent mechanism (196). VI. DIFFERENTIATION OF PIT1 LINEAGES: SOMATOTROPES, LACTOTROPES, AND THYROTROPES A. Pit1 Pit1 is a member of POU domain containing transcription factors. The POU domain consists of a NH2terminal POU-specic domain and a COOH-terminal POU homeodomain, which are both required for high-afnity DNA binding (reviewed in Ref. 9). Pit1 was identied by its specic binding to AT-rich elements in the rat PRL and GH genes. The expression of Pit1 is restricted to the caudomedial region of the pituitary gland. Its expression begins at E13.5 and continues in somatotropes, lactotropes, and thyrotropes throughout adult life. Genetics studies of the Snell (dw) and Jackson (dwj) mice, which carry nature mutations in the Pit1 gene, have established that Pit1 is essential for the terminal differentiation and expansion of three lineages: somatotrope, lactotrope, and thyrotrope, as well as for repressing gonadotrope cell fate (36, 57, 166). Furthermore, Pit1 is necessary for the transcriptional regulation of genes encoding the hormone products of these cell types, including GH, PRL, TSH ,
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and GHRHR (reviewed in Ref. 9). Recently, in zebrash, two null alleles in the pit1 gene have been identied in a systematic screen for genes required for pituitary formation and patterning (110, 201). Somatotropes, lactotropes, and thyrotropes are completely absent in pit1 mutants, which also exhibit expansion of corticotropes and possibly gonadotropes, suggesting that Pit1 function is largely conserved throughout evolution. In humans, mutations in the PIT1 gene are associated with CPHD (reviewed in Refs. 46, 53, 193). B. Regulation of Pit1 Expression The initial activation of the Pit1 gene at E13.5 in anterior pituitary requires the concerted actions of Prop1 and the Wnt/ -catenin signaling and is mediated by an early enhancer located between 5.1 and 10.2 kb upstream of the transcription start site (66, 208). From E16.5, maintenance of Pit1 gene expression requires a distinct autoregulated distal enhancer located at 10 kb upstream of the transcription start site. The distal enhancer contains three functional Pit1 binding sites, a vitamin D receptor binding site, and a retinoic acid (RA) response element that confers Pit1-dependent RA induction (235). In the Snell (dw) mice, Pit1 expression is activated normally at E14.5, but because the Pit protein is defective and autoregulation is therefore nonfunctional, Pit1 expression declines and becomes extinguished in the perinatal period (235). C. Regulation of Somatotrope/Lactotrope Determination Studies of the cis-acting sequences of the rat growth hormone gene (rGH) have established that the minimal information required for selective expression in somatotropes but not lactotropes resides in the proximal 320 bp of the promoter, with as little as 180 bp being sufcient to target reporter in vivo (173). This region contains binding sites for Pit1, thyroid hormone receptor (TR), Sp1, a zinc nger protein Zn-15, and a yet unidentied protein. Extensive mutational analyses in transgenic mice have revealed that multiple elements within this region are essential to mediate GH gene activation in somatotropes and repression in lactotropes, respectively. Sp1 binding site and the zinc nger protein binding site (Z box) are apparently only required for GH activation in somatotropes while 161/ 146 site is required only for GH restriction from lactotropes. On the other hand, thyroid hormone response element (TRE) and Pit1 binding sites (GH-1, 2) are required for both activation in somatotropes and repression in lactotropes. Interestingly, replacing the GH-1 site with the Pit1 binding site (Prl-1P) from the PRL gene results in a loss of restriction from the lactotropes
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without affecting expression in somatotropes. The allosteric effect of Pit1 sites is further supported by the cocrystals of the Pit1 POU domain dimer bound to either GH-1 or Prl-1P sites. The data reveal that the spacing between the DNA contacts made by the POU specic domain and the POU homeodomain of each monomer is increased by 2 bp on the GH-1 site. Deletion of these 2 bp in GH-1 leads to a failure to effectively repress reporter gene expression in lactotropes, suggesting that the conguration of Pit1 bound to the GH-1 site is critical for restriction of GH gene expression in lactotropes. The transcriptional corepressor N-CoR, which can interact with Pit1, has been found by chromatin immunoprecipitation (ChIP) assay to be associated with the nontranscribing GH promoter in nonsomatotrope cells. In addition, overexpression of a dominant negative form of N-CoR in lactotropes results in derepression of the endogenous GH gene. Thus cell type-specic restriction of GH requires combinatorial efforts of Pit1, TR, and an unknown factor that recognizes 161/ 146 site together with the corepressor machinery including N-CoR (254). The 500 bp promoter of human pituitary GH (hGH-N) gene contains binding sites for Pit1, Sp1, and zinc nger proteins. However, it is not sufcient for efcient expression in transgenic mice and a locus control region (LCR), located 14.5 to 32 kb upstream, is required for efcient and position-independent expression of the hGH-N transgene (127). Further dissection of the hGH-N LCR reveals that a 1.6-kb region containing two pituitary specic DNase I hypersensitive sites (HSI and HSII) is sufcient to activate hGH transgene expression. The major functional activity within this region resides in a 404-bp fragment coincident with the HSI, which encompasses three closely spaced Pit1 binding sites (18, 260). All three Pit1 binding sites within the 404-bp fragment contribute to the LCR activity. Furthermore, these three Pit1 sites are sufcient to confer position-independent and somatotropes-restricted 0.5hGH-N transgene activation (261, 262). In pituitary gland of transgenic mice carrying the intact hGH locus, ChIP assays reveal a 32-kb domain of pituitary-specic histone hyperacetylation extending from the LCR to the hGH-N promoter with peaks at HSI and HSII sites. Targeted deletion of a region in HSI that contains two Pit1 sites results in a striking loss of the acetylated domain and a marked reduction of hGH-N transgene expression in the pituitary. Thus the Pit1 sites at HSI play an essential role in the establishment of acetylated active chromatin domain and in the transcriptional activation of the hGH-N gene (112). Interestingly, HSI is also required for the active intergenic Pol II transcription in a domain that includes the hGH-N LCR and adjacent B lymphocyte-specic CD79b gene. Insertion of an exogenous transcriptional terminator within this domain blocks CD79b transcription and represses hGH-N expression without affecting histone acetylation within
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the hGH locus, suggesting that distal LCR transcription plays a critical role in long-range hGH-N activation (35, 113). It certainly will be interesting to appreciate the discrepancy between the rGH and hGH promoters and to determine whether the similar LCR sequence and function are conserved in rodents. D. Regulation of Somatotrope-Specic Gene Expression The rGH gene transcription is strongly stimulated by the TH and by RA via the TRE element that binds TR/ retinoid X receptor (TR/RXR) and RAR/RXR heterodimer. Pit1 interacts strongly with RXR and to a lesser extent with TR and RAR and synergistically regulates the GH promoter (212, 213, 247). The functional signicance of the TRE in regulation of GH expression has been demonstrated in transgenic mice where TRE mutation results in lower reporter gene expression in somatotropes (254). / mutant mice which lack all Consistently, in TR 1 / known TRs, there are reduced numbers of somatotropes in anterior pituitary and reduced serum levels of insulinlike growth factor (IGF) and pituitary GH leading to growth retardation (97). TH-mediated activation of the rGH promoter can be antagonized by a transcriptional repressor zinc nger homeodomain enhancer binding protein Zfhep through a mechanism other than simple competition for binding to the TRE (33). GH expression is also tightly regulated by the hypothalamic factor, growth hormone-releasing hormone (GHRH), through activating the GHRH receptor (GHRHR) expressed on the pituitary somatotropes. Binding of GHRH to its receptor elicits elevated intracellular cAMP levels and subsequently activates the PKA pathway (172). GHRH-stimulated activation of the GH promoter is mediated by PKA-dependent phosphorylation of the transcriptional coactivator CBP, which interacts and synergizes with Pit1 on the Pit1 binding sites (45, 317). The functional signicance of the GHRHR signaling pathway in somatotrope proliferation has been revealed in the little (GHRHRlit/GHRHRlit) mice which carry a single amino acid substitution in GHRHR leading to defective ligand binding, as well as in mice deleted for the GHRH gene. These mutant mice exhibit hypoplastic pituitary gland and GH deciency, causing postnatal growth retardation (5, 93, 172). In humans, mutations in the GHRHR gene are associated with IGHD (reviewed in Ref. 193). Expression of GHRHR in pituitary is dependent on Pit1 as well as Math3, which encodes a bHLH transcription factor and itself is a downstream target of Pit1. Mice decient in the Math3 gene lack GHRHR expression, exhibit defects in somatotropes maturation and proliferation, and are postnatal dwarf (282, 330).
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Analyses of the rat PRL (rPRL) promoter in transgenic mice have demonstrated that 3 kb of 5 -anking region is sufcient to direct lactotrope specic transgene expression and a synergistic interaction between a distal enhancer ( 1.8 to 1.5 kb), and a proximal promoter region ( 422 to 33 bp) is required for high levels of expression (52). The distal enhancer contains four Pit1 binding sites and an estrogen response element (ERE) and has been shown to mediate the synergistic interaction between Pit1 and estrogen receptor (ER) and stimulate PRL transcription in response to estrogen (60, 204, 269). Estrogen-induced PRL expression also requires an intact mitogen-activated protein kinase (MAPK) signaling transduction pathway as interfering with MAPK activation ablates the ability of estrogen to induce PRL expression (303). The in vivo function of ER in regulating PRL expression has been demonstrated in mice deleted for the ER gene. Specication of lactotrope lineage appears normal in these mutant animals; however, there is a marked reduction in PRL mRNA and a decrease in the number of lactotropes (253). The proximal promoter of the PRL gene encompasses binding sites for Pit1, Ets, and Pitx factors and is sufcient to confer cell specic gene expression and mediate regulation by a variety of stimuli. Analyses of the RPL promoter in model cell lines have identied two critical Ets binding sites (EBS): a composite Ets-1/Pit1 binding site located at 212 and an EBS located at 96. The composite Ets-1/Pit1 binding site confers synergy between the two proteins and mediates stimulation by the Ras/MAPK signaling transduction pathway including FGF and thyrotropin-releasing hormone (TRH) (24 26, 116). Pit1 directly interacts with Ets-1. However, the synergy is independent of their physical interaction but requires respective DNA binding sites (71). The synergy between Pit1 and Ets-1 can be blocked by ETS-2 repressor factor (ERF) apparently by preventing Pit1 from binding to the composite site as well as other Pit1 sites (61). The more proximal EBS centered at 96 critical for several growth factor signaling pathways is recognized and activated by ETS factors GABP and GABP (252). Other transcription factors that have been implicated in regulation of the PRL promoter include Pitx factors and CCAAT/enhancer-binding protein (C/EBP ). Both Pitx1 and Pitx2 can interact and synergize with Pit1 in activating several pituitary-specic promoters (7, 278, 290). The synergy between Pitx2 and Pit1 is achieved by Pit1 binding to the COOH-terminal tail of Pitx2 and relieving the autorepression imposed by this region and thereby increasing DNA binding of Pitx2 to a canonical bicoid site (6). Two bicoid sites, B1 and B2, located at 27 and 110,
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respectively, have been identied in the human PRL proximal promoter with the B2 site and two Pit1 binding sites necessary for the synergistic interaction of Pitx2 and Pit1 (224). C/EBP belongs to the bZip family of transcription factors characterized by a conserved COOH-terminal domain containing a basic DNA-binding domain and a leucine zipper that mediates protein-protein interaction. C/EBP can synergize with Pit1 to stimulate the rPRL promoter and the rGH promoter (122). The C/EBP binding site in the PRL promoter overlaps with the proximal EBS which is recognized by GABP /GABP (122). Interestingly, the physical interaction of Pit1 with C/EBP leads to C/EBP redistribution from otherwise centromeric heterochromatin region to nuclear regions occupied by Pit1 (62, 74). PRL expression in pituitary is under the negative control of hypothalamic dopamine via the Gi/o-coupled dopamine D2 receptor (D2R) expressed on lactotropes in pituitary. The inhibitory effects of dopamine on PRL transcription are mediated by antagonizing the elevation of intracellular cAMP or calcium. It has been shown that dopamine treatment leads to a rapid decrease in activated MAPKs, nuclear translocation of ERF, and recruitment of HDAC corepressors to the PRL promoter in cell lines or primary pituitary culture (177, 178). The physiological function of dopamine has been revealed in mice decient in the D2R receptor (Drd2 / mice). These mice have anterior lobe lactotrope hyperplasia and hyperprolactinemia that ultimately leads to lactotrope adenoma in aged animals (139, 242). Conversely, mice lacking the dopamine transporter (DAT), which mediates dopamine reuptake and thereby termination of dopamine action, display hypoplasia of lactotropes and somatotropes, with the latter attributed to the substantial decrease of GHRH expression in hypothalamus (23). Lactotropes are also subject to negative regulation mediated by prolactin receptor (PRLR) signaling via both dopamine-dependent and -independent mechanisms. Prlr / mice exhibit more profound hyperprolactinemia and large prolactinomas than Drd2 / mice, and there are additive effects in compound homozygous mutant male mice. In addition, PRL treatment markedly inhibits lactotrope proliferation in primary mouse pituitary cultures, suggesting an autocrine/paracrine negative regulatory mechanism (249). Recent studies in transgenic zebrash expressing red uorescent protein directed by Prl regulatory elements demonstrate that dopamine-independent PRLR signaling exerts more robust inhibitory effects on embryonic lactotropes than dopaminergic signaling, highlighting the importance of dual peripheral and central interactions for lactotrope proliferation and PRL gene regulation during early pituitary development (180).
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F. Specication of Thyrotrope Lineage The third Pit1-dependent cell lineage, thyrotrope, shares some common features with the non-Pit1-dependent gonadotrope. They arise from the ventral portion of the gland and secrete heterodimeric hormones containing the common GSU subunit and specic -subunits. However, these two lineages appear to diverge at an early stage of pituitary development, such that transcription factors important for cell type-specic hormone expression are present in respective cell type, for example, Pit1 is present in thyrotropes and SF1 in gonadotropes. The plasticity of these two cell types has been demonstrated in several genetic models where gonadotropes can be converted into thyrotropes when Pit1 is ectopically expressed ventrally under the control of GSU regulatory sequences and the Pit1 lineages including thyrotropes adopt the fate of gonadotropes in Snell mice, highlighting the critical function of Pit1 in lineage choice, and also implying that gonadotropes possess the necessary factor(s) for thyrotrope specication (57). The zinc nger transcription factor Gata2, expression of which is under the control of ventral to dorsal BMP2 gradient, is present in both thyrotropes and gonadotropes. Furthermore, Gata2 physically interacts and functionally cooperates with Pit1, leading to synergistic activation of the TSH promoter through adjacent Pit1 and Gata2 binding sites. Extensive transgenic studies have suggested that the unique combination of Pit1 and Gata2 in thyrotropes plays a critical role in TSH expression and thyrotrope specication (57, 95). The in vivo function of Gata2 in pituitary development has recently been investigated by targeted inactivation of Gata2 in the pituitary using a Cre line directed by the GSU regulatory element (42). The mutant mice have fewer thyrotropes and gonadotropes at birth and exhibit reduced production of TSH and FSH in response to the loss of negative feedback by thyroid hormones and steroid hormones, respectively, suggesting that Gata2 is important for optimal thyrotrope and gonadotrope function but not for thyrotrope and gonadotrope cell fate specication, although it remains possible that the function of Gata2 is compensated by Gata3, as in the mutant pituitary gland Gata3 expression is elevated (42). A second thyrotrope lineage, transiently residing in the rostral tip, is Pit1 independent (171). The ontogeny and function of this lineage is largely unknown. A member of the proline and acidic amino acid-rich basic leucine zipper (PAR bZip) transcription factor family, TEF, expressed in rostral tip, is a potent activator of the TSH promoter (70). Expression of all three PAR bZip factors is under the control of circadian rhythms. While deletion of a single factor does not have adverse effects, deletion of all three factors results in epilepsy due to neurotransmitter deciencies, and dramatically shortened life span (85).
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The involvement of TEF and other family members in rostral thyrotrope specication remains to be dened. G. Regulation of GSU Gene Expression GSU is the rst pituitary hormone transcript expressed during development. In mouse, it is rst detected at E10.5 in the most ventral region of the Rathkes pouch. Expression of GSU gene is governed by a series of distinct elements that confer pituitary-specic expression as well as differential expression in thyrotropes and gonadotropes (reviewed in Ref. 128). Analyses of the mouse GSU promoter in transgenic mice have revealed that 381 bp of the promoter is sufcient for expression of a reporter gene in both thyrotropes and gonadotropes, although hormonally and temporally regulated high levels of expression are achieved when 4.6 kb of 5 -anking region is included (29, 140). However, 313 bp of the bovine GSU promoter specically directs expression to gonadotropes in transgenic mice (141), suggesting that the upstream elements confer GSU expression in thyrotropes. The pituitary glycoprotein hormone basal element (PGBE) located from 337 to 330, which is recognized by a LIM-homeodomain transcription factor, such as Lhx3, is necessary for mouse GSU promoter activity in both cell types in cell-based assay and critical for restricting expression to the anterior pituitary (12, 29, 239). Other transcription factors involved in transcriptional regulation of the GSU promoter include the bHLH zipper protein USF, Pitx1/2, and Gata2 which are present in both cell types and interact with elements in the proximal promoter (121, 243, 278, 290). Gonadotrope specic expression of GSU is regulated by SF1 via its cognate binding site, the gonadotrope-specic element (GSE), located at 208 (17, 120). The distal enhancer region located between 4.6 kb and 3.7 kb promotes reporter gene expression in both transgenic mice and in transient transfection assays. Its enhancer activity is dependent on the presence of GSE and PGBE in the proximal promoter in gonadotropes and PGBE in thyrotropes (312). The localized 125-bp enhancer element harbors consensus binding sites for GATA, SF1, Sp1, ETS, bHLH factors, and also mediates GSU repression in cell types other than thyrotropes and gonadotropes, suggesting cooperative interactions between the enhancer and promoter (311). In thyrotropes, expression of GSU is stimulated by TRH and repressed by TH. In the anterior pituitary, binding of TRH to its receptor activates phospholipase C, leading to calcium mobilization and protein kinase C (PKC) activation. It has been shown that Lhx3 plays a pivotal role in mediating TRH signaling by recruiting transcriptional coactivator CBP to the GSU promoter, and the PKC phosphorylation sites in the LIM1 domain of Lhx3 are essential for Lhx3/CBP binding and TRH rewww.prv.org
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sponse (104). In gonadotropes, gonadotropin releasing hormone (GnRH) regulates expression of the GSU gene via two elements in the proximal promoter, PGBE and a second element recognized by an ETS factor which is activated by MAPK pathway in response to GnRH (238). H. Regulation of TSH Gene Expression Transient transfection experiments in thyrotrope cells have shown that the cell-specic activity of the mouse TSH promoter is localized between 270 and 80 of the 5 -anking region (313). Pit1 binds to three sites within this region and is required for the TSH transcription in the caudomedial thyrotropes (171). Other transcription factors functionally cooperating with Pit1 in stimulating the TSH promoter include Lhx3, which is present in all cell types, and Gata2 found only in thyrotropes and gonadotropes (12, 42, 57, 95). Expression of TSH is positively regulated by hypothalamic TRH and inhibited by TH feedback regulation. Recent studies have shown that CBP and Pit1 act synergistically in TRH stimulation of the TSH promoter via Pit1 binding sites (105), and phosphorylation of CBP by PKC is critical for Pit1dependent gene activation (323). TH-dependent negative regulation of TSH transcription is mediated by the -isoform of TR (TR- ) through an element downstream from the transcription start site via recruiting HDAC activity (1, 82, 244). DNA binding activity as well as intact coactivator-interacting surface of TR- are both essential for the feedback regulation, as demonstrated in mice carrying the mutant form of TR- (209, 263). VII. GONADOTROPE DIFFERENTIATION A. SF1 and Other Transcription Factors in Gonadotrope Lineage Differentiation and Function Gonadotrope is the last cell type in the anterior pituitary to reach maturation with the expression of terminal differentiation markers LH , FSH , and GnRHR. The specication of gonadotrope cell fate, however, occurs a few days earlier with the onset of SF1 expression at E13.5 (120). Transgenic studies have localized an enhancer element in the sixth intron of SF1 conferring pituitary specic expression (264). SF1 is also expressed in developing gonads, adrenal glands, and ventromedial hypothalamic nucleus (VMH). It encodes a zinc nger nuclear receptor directly regulating a large number of genes involved in sex determination and differentiation, steroidogenesis, and reproduction including GSU, LH , FSH , and GnRHR. Recent studies have revealed that phospholipids bind to the ligand-binding pocket of SF1 with phosphatidylinosiPhysiol Rev VOL
tol 3-kinase-derived phosphatidylinositols [PtdIns(4,5)P2 and PtdIns(3,4,5)P3] delineated as high-afnity preferred ligands. Mutations intended to interfere with ligand binding abolish coactivator recruitment and impair SF1 transcriptional activity, implicating that the function of SF1 is likely to be modulated in vivo by endogenous ligands (153, 169, 298). While the regulation of SF1 activity is an exciting new area, the physiological function of SF1 has long been established by targeted disruption, which leads to adrenal and gonadal agenesis, defective differentiation of the VMH, and impaired expression of LH , FSH , and GnRHR in pituitary (120, 265; reviewed in Ref. 215). Pituitary-specic inactivation of SF1 recapitulates the SF1 / pituitary phenotype and results in sterile mice with hypoplastic gonads (324, 325). However, expression of LH and FSH in SF1 / mutant mice can be restored by GnRH treatment, arguing that SF1 is not necessary for gonadotrope cell fate specication (119, 325). The GnRH compensation for the LH expression in SF1 / mice has been suggested to be mediated by Egr1, a GnRH-inducible zinc nger transcription factor that can synergize with SF1 to activate the LH promoter (163, 288). Egr1 is preferentially expressed in somatotropes, thyrotropes, and gonadotropes. Mice decient for Egr1 exhibit reduced numbers of somatotropes and diminished expression of LH (163, 284). However, gonadotrope differentiation in Egr1 / mice occurs normally with FSH expression, consistent with a direct role of Egr1 in regulating LH transcription. Extensive studies using transgenic mice have suggested that Gata factors, such as Gata2, expression of which precedes SF1, may play a role in gonadotrope differentiation. Ectopic expression of Gata2 in Pit1 lineages leads to repression of Pit1 and subsequent gonadotrope conversion while overexpression of dominant negative form of Gata2 blocks differentiation of both thyrotrope and gonadotrope (57). However, as noted above, pituitary-specic inactivation of Gata2 leads to reduced secretion of gonadotropins basically and in response to the loss of negative feedback by steroid hormones without affecting terminal differentiation of gonadotropes. The mild effect of deleting Gata2 is likely to be due to functional compensation by Gata3, although it remains to be determined whether Gata2 and Gata3 function together in lineage specication (42). While no single transcription factor has been demonstrated to be necessary and sufcient for gonadotrope lineage commitment, other transcription factors, in addition to SF1, Egr1, and Gata2, have been implicated in regulating gonadotropes function, including Pitx1, Pitx2, Prop1, and Otx1. Otx1 is expressed in postnatal pituitary, and transient transfection experiments indicate that Otx1 can specically activate promoters of GH, GSU, LH , and FSH . Mice decient for Otx1 exhibit transient dwarsm and hypogonadism at the prepubescent stage
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due to the selective and transient reduction of GH, FSH, and LH in pituitary, suggesting a differential requirement of transcription factors at different developmental stages (2). B. Transcriptional Regulation of Gonadotrope Specic Genes 1. FSH gene regulation FSH is a major regulator of gonadal development. It is required for oogenesis in females and is important for spermatogenesis in males. The basal expression of FSH is regulated by Lhx3, Pitx1, heterotrimeric nuclear factor-Y (NFY), and SF1. Lhx3 can activate the porcine FSH promoter by recognizing multiple elements within the promoter. These sites, however, are not required for the activin response in L T2 gonadotrope cells (305). Pitx1 has been demonstrated to activate the rat FSH gene promoter both basally and in synergy with GnRH by binding to a vital site ( 54) in the promoter and by a DNAbinding independent mechanism (322). Both Lhx3 and Pitx1 are expressed in multiple cell lineages in pituitary; gonadotrope-specic expression of FSH is conferred by SF1. It has been shown that SF1 physically and functionally interacts with ubiquitously expressed NFY contributing to basal activity of the mouse FSH promoter via the upstream elements (123). Expression of FSH is primarily regulated by GnRH, gonadal steroids, and members of the TGF- superfamily including activins (reviewed in Ref. 32). Mice with lossof-function mutation in either GnRH or GnRHR gene have low levels of LH and FSH in pituitary (39, 216). Binding of GnRH to its receptor on the gonadotrope membrane activates the PKC and MAPK signaling pathways and induces transcription of the early response genes, c-fos, c-jun, and Egr1 (49). Two conserved AP1-like sites, located in the proximal promoter of the ovine FSH gene, are necessary to mediate GnRH responsiveness in heterologous cells. However, they are not required in L T2 gonadotrope cell line and in transgenic mice in the context of 4741 bp to 753 bp of ovine FSH promoter (reviewed in Refs. 192, 294). In L T2 cells, GnRH response is mediated by two distal elements (between 4152/ 2878 and 2550/ 1089 bp) in association with elements within the proximal region of the ovine FSH promoter (294). A recent study has identied a GnRH responsive element in the proximal promoter of mouse FSH gene consisting of an AP-1 half-site ( 72/ 69) and juxtaposed NFY binding site ( 76). Activin, a signaling protein secreted by the gonads and the pituitary, is a potent inducer of FSH transcription through binding to transmembrane serine/threonine kinase receptors. Mice decient for Acvr2a (activin receptor type IIA) exhibit diminished levels of FSH in
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pituitary (189). Smad2 and Smad3 are the principal mediators of activin signaling. Upon phosphorylation induced by activin, Smad2 and Smad3 associate with common mediator Smad4 and translocate into nucleus to regulate gene transcription. Smad3 plays a key role in activininduced FSH transcription (20, 275). A Smad-binding element (SBE) has been identied in the rat FSH promoter ( 281/ 253) to mediate Smad3-induced reporter activity (98, 276). However, the critical SBE is conserved only in rodent species. In the ovine FSH promoter, there are three regions ( 973/ 962, 167, and 134) required for full activin responsiveness (14). The distal site binds Smad4 protein, and the critical 134 site binds the TALE homeodomain proteins Pbx1 and Prep1 in association with Smad4, and the two proximal activin responsive elements are conserved across species and are bound by Pbx1 and Prep1 in the mouse gene (14). Pituitary-restricted regulation of FSH by activin can be conferred by Pitx2, which enhances both basal and activin/Smad3induced activation of rat FSH promoter by interacting with a Pitx1 binding site ( 230/ 199) (276). 2. LH gene regulation LH regulates folliculogenesis, ovulation, gametogenesis, and gonadal steroidogenesis. Transgenic studies have shown that 776 bp of bovine LH promoter is sufcient to direct gonadotrope-specic expression and confer regulation by GnRH and gonadal steroids (144). The proximal 140 bp of the LH promoter are remarkably conserved across species, whereas distal regions diverge depending on species. Within the conserved region, there are two SF1 binding sites (GSE, 58/ 51, 127/ 119), two Egr1 sites ( 49/ 41, 112/ 104), and one Pitx site ( 99/ 96) critical for LH expression (100, 101, 143, 225, 288, 309, 310; reviewed in Ref. 128). Each of the transcription factors that recognizes respective sites, SF1, Egr1, and Pitx1, can function alone or in synergy with others in activating the LH promoter through direct physical interactions (100, 288). The functional signicance of the distal SF1 binding site and the Pitx1 binding site in vivo has been demonstrated in transgenic mice (143, 225). In the L T2 gonadotrope cell line, the Pitx1 binding site is recognized by an unknown OTX-class homeodomain factor (241). A second putative Pitx1-binding site ( 65/ 60) in the rat LH promoter has recently been identied to mediate Pitx1-induced promoter activity and to contribute to the synergy between Pitx1 and SF1 (125). The distal region of the bovine LH promoter contains two NFY binding sites with different afnity. The more distal highafnity NFY site is critical for conferring high basal activity of the LH promoter (142). Expression of LH is stimulated by GnRH. GnRH responsiveness of the LH promoter is achieved in part by transient induction of Egr1 and the synergy between
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FIG. 2. A: the hypothalamic-pituitary axis. The magnocellular neurosecretory system includes neurons in paraventricular hypothalamus (PVN) and supraoptic nucleus (SON) that synthesize oxytocin (OT) and arginine vasopressin (AVP) and release them from axonal terminals in the posterior lobe (P). Hormone synthesis and secretion in the anterior lobe of pituitary (A) are regulated by releasing factors produced by the parvocellular neurons and released into the portal vascular system. Corticotropin releasing hormone (CRH) and thyrotropin releasing hormone (TRH) are synthesized by neurons in the PVN. Growth hormone releasing hormone (GHRH) is synthesized by neurons of the arcuate nucleus (ARN) and the adjacent ventromedial nucleus. Somatostatin (SS) is mainly synthesized by neurons in anterior periventricular nucleus (aPV). The parvocellular neurons project to the medial eminence where they release hormones that are transported to the anterior pituitary by the portal vascular system. B: genetic hierarchy of hypothalamic neuron formation. [Modied from Dasen and Rosenfeld (58).]
Egr1, SF1, and Pitx1 (68, 102, 143, 225, 288, 310). The zinc-nger transcription factor Sp1 interacts with two GC-rich elements within the distal region of the rat LH promoter. Mutation of the Sp1-binding sites diminishes GnRH-induced activation of the promoter (130). Combined mutations in Sp1, SF1, and Egr1 binding sites have determined that these sites are required for full GnRH responsiveness, suggesting that communication exists between the distal and proximal regions of the rat LH promoter to mediate GnRH responsiveness (129). VIII. THE HYPOTHALAMIC/PITUITARY REGULATORY SYSTEM The physiological function of anterior pituitary is regulated by hypothalamic releasing hormones, which are secreted by the parvocellular neurons. CRH and TRH are synthesized by neurons in the paraventricular (PVN) nucleus. GHRH is synthesized by neurons of the arcuate nucleus and the adjacent ventromedial nucleus. SomaPhysiol Rev VOL
tostatin (SS) is mainly synthesized by neurons in the anterior periventricular nucleus (aPV). GnRH is synthesized by neurons located in the preoptic region. The parvocellular neurons project to the medial eminence where they release hormones that are conveyed to the anterior pituitary by the hypophysial-portal vasculature. The magnocellular neurons, the second set of neuroendocrine neurons of hypothalamus, are located in two nuclei of the anterior hypothalamus, the paraventricular (PVN) and the supraoptic (SON) nuclei. They project to the posterior pituitary where they release vasopressin (AVP) and oxytocin (OT) directly into the general circulation. Induction and patterning of the hypothalamus is regulated by HH, Nodal, BMP, and Wnt signals as well as unidentied stimulus from Rathkes pouch (55, 131, 207; reviewed in Ref. 308). Functional studies have revealed that the ventral diencephalon is instrumental for the formation of Rathke pouch in part by producing signaling molecules including FGF, BMP, and Wnt. Here we discuss a number of hypothalamic specic factors that are rewww.prv.org
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quired for pituitary functions (Fig. 2). These factors, together with the signaling molecules and transcription factors critical for pituitary development, are summarized in Table 1. A. Sox3 and the Morphogenesis of Pituitary The HMG box transcription factor Sox3 and Sox2, members of the SoxB1 subfamily, are coexpressed in all neural precursors during CNS development. During pituitary development, they are expressed in the ventral diencephalon and throughout infundibulum. Sox2 is also expressed in Rathkes pouch. Targeted deletion of Sox3 results in variable and pleiotropic defects, including craniofacial abnormalities, midline CNS defects, and hypopituitarism. In Sox3 / mutant mice, expression domain of FGF8 and BMP4 in the ventral diencephalon is expanded, which is accompanied by reduced proliferation and evagination of the infundibulum, leading to bifurcation of Rathkes pouch and anterior pituitary dysmorphology with extra clefts. There is a reduction in the levels of GH, LH, FSH, and TSH in the pituitary. The pituitary defect is suggested to result, at least in part, from a later requirement for Sox3 within the hypothalamus neurons (236, 237). Inactivation of Sox2 leads to early lethality at peri-implantation stages precluding further analysis. Examinations of Sox2 / mice have revealed bifurcation of Rathkes pouch during pituitary development. The mutant mice also exhibit extra clefts in the pituitary with moderately reduced levels of pituitary LH and GH, implying a dosage-sensitive requirement for Sox2 in the pituitary development (138, 237). In humans, mutations in SOX3 are associated with X-linked mental retardation and GH deciency, and mutations in SOX2 are associated with abnormalities in the hypothalamopituitary and reproductive axes (138, 161, 272). B. Specication of GHRH Neurons: Hmx2/3 and Gsh-1 The homeodomain transcription factor Gsh-1 can bind to multiple sites in the rat GHRH promoter and stimulate promoter activity alone or in synergy with coactivator CBP (195). It is expressed in the neural tube, hindbrain, mesencephalon, and diencephalon of the developing CNS. Mice decient for Gsh-1 exhibit signicant postnatal dwarsm due to a failure of GHRH expression in the arcuate nucleus of the hypothalamus and subsequent GH deciency. In the Gsh-1 / mutant pituitary, in addition to reduced numbers of somatotropes as seen in the little mouse, the number of lactotropes is also decreased and the levels of LH are reduced, which may contribute to sexual infantilism of the Gsh-1 / mutant,
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suggesting that Gsh-1 is required for multiple processes in addition to regulating GHRH expression (164). Two members of the Hmx homeodomain transcription factors, Hmx2 and Hmx3, are required to maintain Gsh-1 expression in hypothalamus. They are coexpressed in developing inner ear, CNS including hypothalamus, and neural tube. They exert both overlapping and distinct functions in the development of the inner ears vestibular system, whereas their functions in hypothalamic/pituitary axis appear to be redundant. Deletion of either Hmx2 or Hmx3 results in defects in the inner ear without overt abnormalities in the nervous system. Inactivation of both Hmx2 and Hmx3 leads to progressive degeneration of the entire vestibular system, postnatal growth retardation, and early lethality. Expression of GHRH and galanin, a neuropeptide hormone regulating food intake, memory, learning, as well as sexual activity, in the arcuate nucleus is completely abolished. Secondary to the defects in the hypothalamus, the anterior pituitary of Hmx2 / Hmx3 / is hypoplastic with reduced expression of GH and progressive loss of Lhx3 expression (296). C. Genetic Hierarchy of Magnocellular Neuron Formation: Otp, Sim1/Arnt2, Sim2/Arnt2, and Brn2 The POU homeodomain transcription factor Brn2 is essential for the terminal differentiation and/or survival of the AVP- and OT-producing magnocellular neurosecretory cells in SON and PVN as well as CRH-producing parvocellular neurons in PVN. Given that Brn2 binds and activates the CRH promoter, it is suggested that Brn2 controls the development of these lineages at the terminal stage of their differentiation (165, 248). Loss of magnocellular neurons in Brn2 / results in lack of axonal projections and progressive loss of pituicytes, the astroglial cells of the posterior lobe of the pituitary (198, 248). The bHLH-PAS transcription factor Sim1 is expressed during the development of the hypothalamic-pituitary axis in three hypothalamic nuclei: PVN, aPV, and SON. In Sim1 / mice, the entire magnocellular neurosecretory system, which secretes AVP and OT, and three major types of parvocellular neurosecretory cells, identied by the synthesis of TRH, CRH, and SS, fail to develop. Expression of Brn2 is downregulated in a region of the prospective PVN/SON, suggesting that Sim1 is required to maintain Brn2 expression, which in turn directs the terminal differentiation of neuroendocrine lineages within the PVN and SON (191). Sim2, the homolog of Sim1, is coexpressed with Sim1 in dorsal preoptic area (dP), aPV and anterior and mid-PVN, where SS and TRH-expressing neurons reside. Targeted disruption of Sim2 leads to a reduction in the number of SS and TRH neurons, and this phenotype is
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TABLE
1. Signal pathways and transcription factors critical for pituitary and hypothalamus development and function
Functions Gene Expression Mouse/Zebrash Pituitary Phenotypes Reference Nos.
BMP4 FGF10 FGFR2-IIIb Fgf 3 Wnt4 Wnt5a SHH
VD VD RP VD RP VD VD, oral ectoderm except RP Hypothalamus Anterior pituitary Hypothalamus Anterior pituitary Pituitary Pituitary Pituitary Pituitary Pituitary VD and RP RP RP RP RP
KO Pitx1-Noggin Tg KO KO lia (zebrash) KO KO Pitx1-HIP Tg sonic-you (syu, zebrash) KO Little, KO hpg, deletion Mutation KO KO KO KO KO KO KO KO KO KO
GHRH GHRHR GNRH GNRHR Drd2 ACR2 Prlr LIFR PTP Hesx1 Pitx1 Pitx2 Isl1 Lhx3
Signaling transduction pathways RP fails to form, embryonic lethal RP arrested at e10 with loss of all cell types except corticotropes Anterior pituitary agenesis due to increased apoptosis Anterior pituitary agenesis due to increased apoptosis Increased apoptosis leading to a complete loss of pituitary Hypoplastic pituitary with marked reduction of Pit1 lineages Pituitary dysmorphogenesis; cell differentiation occurs normally Pituitary hypoplasia with loss-of-expression of ventral transcription factors Hypoplastic pituitary with reduced POMC- and PRL-positive cells and absence of GH and TSH-positive cells IGHD, hypoplastic pituitary with reduced production of GH IGHD, postnatal dwarf, reduced proliferation of caudomedial somatotropes Decreased LH , FSH , ACTH, PRL in pituitary Dramatic reduction in the numbers of FSH- and LH-producing gonadotropes Prolactinomas Reduced expression of FSH Hyperprolactinemia and large prolactinomas Reduced expression of POMC in pituitary Transient reduction of GH and PRL Transcription factors/cofactors Absence of pituitary or multiple oral ectoderm invagination and cellular Decreased expression of LH , FSH , TSH ; increased expression of POMC RP forms but fails to proliferate and differentiate at e12.5; lacks all cell types except corticotropes RP forms but remains primitive, thin pouch wall, embryonic lethal Hypoplastic anterior pituitary with reduction of all cell types; increased apoptosis. Lhx3 and Lhx4 DKO fail to form a denite pouch Hypoplastic anterior pituitary with reduction of all cell types, increased apoptosis Hypoplastic pituitary No pituitary phenotype. Six1 and Eyal DKO have smaller pituitaries Impaired corticotrope, melanotrope and gonadotrope differentiation; fail to maintain gh and tsh expression Dorsal expansion of ventral cell types at the expense of dorsal cell types. No GnRH-1 neurons All pituitary cell types fail to differentiate; lack pit1 expression Delayed corticotropes differentiation Reduced corticotropes and melanotropes; melanotropes transdifferentiate into gonadotropes and Pit1-independent thyrotrope Reduced proliferation and premature corticotropes differentiation; intermediate lobe fails to develop; no posterior lobe Markedly reduction of Prop1; Pit1 lineages adopt the corticotrope cell fate No Pit1 activation, lack three Pit1 lineages; reduced LH and FSH Loss of Pit1 expression and Pit1 lineages; reduced LH expression Elevated Pit1, GH, and TSH expression Hyperplastic anterior pituitary, prolonged Prop1 expression Loss of somatotropes, thyrotropes, and lactotropes and increased gonadotropes Loss of somatotropes, thyrotropes, and lactotropes and expanded corticotropes Loss of Ghrhr expression, delayed somatotropes maturation
279 285 206 234 110 285 41 286 111, 149, 246 5 172 39 216 139, 242 189 249 300 73 59, 187 277 88, 170 279 259, 326
Lhx4 Six6 Six1 eya1 Pax6 ascl1a NeuroD1 Tbx19
RP RP RP Pituitary RP Pituitary RP POMC precursors RP RP RP RP RP RP Pit1 lineages
KO KO KO aal, dog (zebrash) KO pia (zebrash) KO KO
227, 257 168 167 202 19, 147 219 157 222, 223
Hes1 Rbp-J Prop1 -catenin Lef1 Tcf4 Pit1
KO CKO KO, Ames CKO KO KO Snell, Jackson pit1 (zebrash)
330 330 199, 273, 299 208 208 30 36, 57, 166 201 330
Math3
Anterior pituitary
KO
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TABLE
953
1.Continued
Functions
Gene
Expression
Mouse/Zebrash
Pituitary phenotypes
Reference Nos.
ERa TR GR Aes Sf1 Egr1 Otx1 Sox3 Sox2 Titf1 Gli2
Pituitary Pituitary Pituitary RP Gonatotrope Pituitary Postnatal Pituitary VD VD, RP VD VD, RP
KO KO KO KO KO KO KO KO heterozygous KO KO you-too (zebrash) KO KO KO KO KO KO KO KO
Brn2 Otp Sim1 Sim2 Arnt2 Hmx2, 3 Gsh1 Nhlh2
Hypothalamus Hypothalamus Hypothalamus Hypothalamus Hypothalamus Hypothalamus Hypothalamus Hypothalamus Pituitary Hypothalamus
Ebf2
KO
Decreased number of lactotropes and reduced PRL expression Reduced number of somatotropes in mice lacking all TR. Elevated TSH in pituitary in TR- / Increased POMC expression in corticotropes Pituitary dysmorphogenesis Impaired pituitary FSH and LH expression No LH expression; reduced number of somatotropes Transient dwarsm, delayed production of LH, FSH, and GH Reduced GH levels and dysmorphic anterior lobe Dysmorphic anterior lobe Absence of pituitary due to ablation of the FGFs expression domain in VD Variable loss of pituitary; DKO of Gli1 and Gli2 causes complete loss of pituitary Pituitary transdifferentiation into a lens Loss of posterior pituitary due to defects in survival of hypothalamus neurons Reduced neuroblast proliferation; defective magnocellular and parvocellular Magnocellular neurons and some parvocellular neurons fail to develop Reduced TRH and SS neurons; defective magnocellular and parvocellular neurons Magnocellular neurons and some parvocellular neurons fail to develop Reduced GHRH and GH production Hypoplastic anterior pituitary; reduced production of GHRH, GH, PRL and LH Hypogonadal; reduced production of FSH; adult-onset obesity. DKO of Nhlh1 and Nhlh2 results in signicant reduction of GnRH-1 neurons Defective GnRH-1 neurons migration
253 1, 97 231, 232 30 120, 265 163 2 236 138 145, 279 214 149 248 3, 297 191 96 115, 137, 190 296 164 94, 126, 152
48
VD, ventral diencephalon; RP, Rathkes pouch; Tg, transgenic; KO, knockout; DKO, double knockout.
Sim2-dosage sensitive. The interplay between Sim1 and Sim2 is complex. Genetic analysis indicates that Sim2 acts downstream of Sim1, yet Sim1 can partially compensate for the loss of Sim2 (96). Sim1 and Sim2 can form heterodimer with aryl hydrocarbon receptor nuclear translocator (Arnt), Arnt2, and Bmal1 (190). Arnt is broadly expressed in the mesoderm and endoderm, but only at a low level in the CNS. Disruption of Arnt leads to embryonic lethality at E10.5 associated with placental, vascular, and hematopoietic defects. Bmal1 expression is not detectable in the PVN and SON but instead is restricted to the SCN in this region of the hypothalamus (190). In contrast, Arnt2 is ubiquitously expressed in the hypothalamus with abundant expression in PVN and SON. Inactivation of Arnt2 results in a strikingly similar phenotype to that of Sim1 / , suggesting that Arnt2 is the in vivo dimerization partner of Sim1 and they function together in controlling differentiation of aPV, PVN, and SON neurons (115, 137, 190). Arnt2 is also proposed to be the in vivo partner of Sim2 (96). Otp, which encodes a homeodomain transcription factor, exhibits an overlapping pattern of expression with Sim1 except that Otp is also expressed in the ARN.
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Studies of the Otp / mice reveal that Otp, in parallel to Sim1, is required for both terminal differentiation of parvocellular and magnocellular neurons of aPV, PVN, and SON and for maintenance of Sim2 and Brn2 expression. Otp is also required for producing SS in ARH neurons. Before terminal differentiation impairments, Otp / mice display reduced cell proliferation of neuroblasts and abnormal migration of postmitotic neurons, suggesting that Otp may exert its functions at early stages leading to the establishment of the neuroendocrine hypothalamus (3, 297). D. Specication and Migration of GnRH-1 Neurons The GnRH-1 neurons control reproductive axis by projecting axons to the median eminence, where they secrete the GnRH-1 decapeptide in a pulsatile manner into the hypophysial blood system to regulate expression of LH and FSH . They are generated from the olfactory placodes, although recent studies in sh and chicken suggest that they originate from the neighboring domain where the anterior pituitary arises (reviewed by Ref. 306).
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They migrate along vomeronasal nerves (VNN) across the cribriform plate to their ultimate destination scattered in the hypothalamic region of the basal forebrain late in embryonic development (reviewed in Refs. 183, 307, 314). Failure of GnRH-1 neurons to produce GnRH-1 or to migrate appropriately results in reduced levels of LH and FSH and subsequent reproductive dysfunction. It has been shown that Pax6 is required for the generation of GnRH-1 neurons. In the small-eye mouse mutant (Sey/Sey), which results from a mutation in the Pax6 gene, both optical and olfactory placodes fail to develop (114). The pituitary forms, however, with defects in the dorsal-ventral patterning and cell type specication (19, 147). GnRH-1 neurons are absent in either the presumptive nasal area or in any region of brain during development (65). GnRH-1 neurons must travel over long distances and various environments to reach their destination. Many in vivo and in vitro studies have revealed a number of molecules inuencing their migration. Some of these molecules affect the migration of GnRH-1 neurons indirectly by altering the underlying migratory trajectory (reviewed in Refs. 281, 307). For example, axonal guidance molecule netrin 1 is expressed in the caudal olfactory epithelium and ventral forebrain, whereas DCC (deleted in colorectal cancer), a netrin 1 receptor, is present on vomeronasal nerves that extend toward forebrain. Inactivation of either netrin 1 or Dcc results in aberrant growth of caudal VNN and abnormal migration of GnRH-1 neurons (250, 251). In humans, two genes have been identied as responsible for the Kallmanns syndrome (KS), characterized by anosmia and hypogonadotropic hypogonadism. Anosmia is related to the absence or hypoplasia of the olfactory bulbs. Hypogonadism is due to GnRH deciency and is likely to result from the impairment in the migration of GnRH-1 neurons. The gene underlying the X-linked form of this syndrome, KAL-1, is expressed in the anlagen of the olfactory bulbs. KAL-1 encodes a putative adhesion molecule named anosmin-1 that can induce the migration of immortalized GnRH neurons in vitro (37). More recently, loss-of-function mutations in FGFR1 have been established to account for an autosomal dominant form of KS (reviewed in Ref. 67). Inactivation of Fgfr1 in the telencephalon in mice results in a failure in olfactory bulb formation (107). Although it is possible that the GnRH-1 neuron migration defect in KS could be secondary to olfactory abnormality, other studies have implicated a direct role of FGF signaling in maintaining GnRH-1 neurons. FGF receptors are expressed in a subpopulation of GnRH neurons in mouse, and expression of a dominant negative form of Fgfr1 in GnRH neurons leads to a reduction in the number of GnRH neurons. However, migration of the remaining GnRH-1 neurons is apparently not affected in the transgenic mice (292).
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Gene targeting in mouse has revealed two classes of transcription factors that are critical for GnRH-1 neuron migration and survival. Ebf2, encoding a transcription factor with a zinc-nger DNA binding domain and a COOH-terminal HLH dimerization domain, is expressed both in GnRH and vomeronasal neurons. In Ebf2 / mice, GnRH neurons migrate slowly out of the vomeronasal organ and are ectopically located in the forebrain at birth. The defect in GnRH neuron migration leads to impaired hypothalamus-pituitary axis and secondary hypogonadism (48). Nhlh1 and Nhlh2, members of the basic HLH transcription factors, are expressed in largely overlapping patterns in different areas of the central and peripheral nervous systems during the embryonic and perinatal stages, including hypothalamic GnRH-1 neurons. Nhlh2 / mice are hypogonadal and infertile due to a reduction in the number of GnRH-1 neurons and projecting axons in the median eminence (94, 126, 152). In contrast, Nhlh1 / mice are fertile and develop normally with no apparent morphological abnormality (151). Combined inactivation of Nhlh1 and Nhlh2 leads to a dramatic loss of GnRH-1 neurons and a complete absence of GnRH1-positive bers within the median eminence. Because there are no apparent defects in vomeronasal nerves, it is proposed that Nhlh1 and Nhlh2 control differentiation/ migration of GnRH-1 neurons in a cell autonomous manner by regulating downstream target genes. One of the downstream targets is necdin, which is deleted in human Prader-Willi syndrome, characterized by obesity and infertility (152). Disruption of the mouse necdin gene results in a reduction of GnRH-1 neurons resembling the Nhlh2 mutation (194). IX. CONCLUSIONS Genetic studies (loss-of-function and gain-of-function), in combination with molecular and biochemical studies, have elucidated a primary sketch in which signaling molecules and transcription factors govern proper pituitary development and function. However, the large network required for these events remains incompletely dened, for example, what are the signals guiding the commitment of corticotropes, gonadotropes, and melanotropes? How do Pit1 precursors embark on three different differentiation programs? Generation of temporally regulated tissue-specic deletion of genes or hypomorphic allele of genes that are necessary for early embryonic development will reveal new functions. Genome-wide mutagenesis screen in mice and model organisms, combined with integrated genomic, proteomic, and bioinformatics approaches, will certainly uncover novel players in this elaborately regulated genetic program. Identication of required cofactors as well as downstream target genes of the transcription factors and complementary studies in
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epigenetic regulation of chromatin organization and nuclear architecture will delineate the molecular mechanisms underlying pituitary development, uncovering new principles of mammalian organogenesis.
ACKNOWLEDGMENTS
13.
14.
We apologize to colleagues whose work is not cited due to space limitations. We thank J. Hightower for gure preparation. Address for reprint requests and other correspondence: M. G. Rosenfeld and/or X. Zhu, Howard Hughes Medical Institute, Department and School of Medicine, Univ. of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093 (e-mails: mrosenfeld@ucsd.edu; xizhu@ucsd.edu).
GRANTS
15. 16.
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M. G. Rosenfeld is an investigator with the Howard Hughes Medical Institute. Studies in M. G. Rosenfelds laboratory are supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases.
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REFERENCES
1. Abel ED, Boers ME, Pazos-Moura C, Moura E, Kaulbach H, Zakaria M, Lowell B, Radovick S, Liberman MC, Wondisford F. Divergent roles for thyroid hormone receptor beta isoforms in the endocrine axis and auditory system. J Clin Invest 104: 291300, 1999. 2. Acampora D, Mazan S, Tuorto F, Avantaggiato V, Tremblay JJ, Lazzaro D, di Carlo A, Mariano A, Macchia PE, Corte G, Macchia V, Drouin J, Brulet P, Simeone A. Transient dwarsm and hypogonadism in mice lacking Otx1 reveal prepubescent stagespecic control of pituitary levels of GH, FSH and LH. Development 125: 1229 1239, 1998. 3. Acampora D, Postiglione MP, Avantaggiato V, Di Bonito M, Vaccarino FM, Michaud J, Simeone A. Progressive impairment of developing neuroendocrine cell lineages in the hypothalamus of mice lacking the Orthopedia gene. Genes Dev 13: 27872800, 1999. 4. Akita S, Readhead C, Stefaneanu L, Fine J, TampanaruSarmesiu A, Kovacs K, Melmed S. Pituitary-directed leukemia inhibitory factor transgene forms Rathkes cleft cysts and impairs adult pituitary function. A model for human pituitary Rathkes cysts. J Clin Invest 99: 24622469, 1997. 5. Alba M, Salvatori R. A mouse with targeted ablation of the growth hormone-releasing hormone gene: a new model of isolated growth hormone deciency. Endocrinology 145: 4134 4143, 2004. 6. Amendt BA, Sutherland LB, Russo AF. Multifunctional role of the Pitx2 homeodomain protein C-terminal tail. Mol Cell Biol 19: 70017010, 1999. 7. Amendt BA, Sutherland LB, Semina EV, Russo AF. The molecular basis of Rieger syndrome. Analysis of Pitx2 homeodomain protein activities. J Biol Chem 273: 20066 20072, 1998. 8. Andersen B, Pearse RV, 2nd Jenne K, Sornson M, Lin SC, Bartke A, Rosenfeld MG. The Ames dwarf gene is required for Pit-1 gene activation. Dev Biol 172: 495503, 1995. 9. Andersen B, Rosenfeld MG. POU domain factors in the neuroendocrine system: lessons from developmental biology provide insights into human disease. Endocr Rev 22: 235, 2001. 10. Ando Z, Sato S, Ikeda K, Kawakami K. Slc12a2 is a direct target of two closely related homeobox proteins, Six1 and Six4. FEBS Lett 272: 3026 3041, 2005. 11. Bach I, Carriere C, Ostendorff HP, Andersen B, Rosenfeld MG. A family of LIM domain-associated cofactors confer transcriptional synergism between LIM and Otx homeodomain proteins. Genes Dev 11: 1370 1380, 1997. 12. Bach I, Rhodes SJ, Pearse RV 2nd, Heinzel T, Gloss B, Scully KM, Sawchenko PE, Rosenfeld MG. P-Lim, a LIM homeodomain factor, is expressed during pituitary organ and cell commitment Physiol Rev VOL
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
and synergizes with Pit-1. Proc Natl Acad Sci USA 92: 2720 2724, 1995. Baek SH, Kioussi C, Briata P, Wang D, Nguyen HD, Ohgi KA, Glass CK, Wynshaw-Boris A, Rose DW, Rosenfeld MG. Regulated subset of G1 growth-control genes in response to derepression by the Wnt pathway. Proc Natl Acad Sci USA 100: 32453250, 2003. Bailey JS, Rave-Harel N, McGillivray SM, Coss D, Mellon PL. Activin regulation of the follicle-stimulating hormone beta-subunit gene involves Smads and the TALE homeodomain proteins Pbx1 and Prep1. Mol Endocrinol 18: 1158 1170, 2004. Baker CV, Bronner-Fraser M. Vertebrate cranial placodes. I. Embryonic induction. Dev Biol 232: 1 61, 2001. Barabanov VM, Fedtsova NG, Minina TA. [Detection of the competence of the lateral head ectoderm of chick embryos for adenohypophysis differentiation.] Dokl Akad Nauk SSSR 265: 196 199, 1982. Barnhart KM, Mellon PL. The orphan nuclear receptor, steroidogenic factor-1, regulates the glycoprotein hormone alpha-subunit gene in pituitary gonadotropes. Mol Endocrinol 8: 878 885, 1994. Bennani-Baiti IM, Asa SL, Song D, Iratni R, Liebhaber SA, Cooke NE. DNase I-hypersensitive sites I and II of the human growth hormone locus control region are a major developmental activator of somatotrope gene expression. Proc Natl Acad Sci USA 95: 1065510660, 1998. Bentley CA, Zidehsarai MP, Grindley JC, Parlow AF, BarthHall S, Roberts VJ. Pax6 is implicated in murine pituitary endocrine function. Endocrine 10: 171177, 1999. Bernard DJ. Both SMAD2 and SMAD3 mediate activin-stimulated expression of the follicle-stimulating hormone beta subunit in mouse gonadotrope cells. Mol Endocrinol 18: 606 623, 2004. Bhangoo AP, Hunter CS, Savage JJ, Anhalt H, Pavlakis S, Walvoord EC, Ten S, Rhodes SJ. A novel LHX3 mutation presenting as combined pituitary hormonal deciency. J Clin Endocrinol Metab 91: 747753, 2006. Bilodeau S, Vallette-Kasic S, Gauthier Y, Figarella-Branger D, Brue T, Berthelet F, Lacroix A, Batista D, Stratakis C, Hanson J, Meij B, Drouin J. Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC gene and misexpression in Cushing disease. Genes Dev 20: 28712886, 2006. Bosse R, Fumagalli F, Jaber M, Giros B, Gainetdinov RR, Wetsel WC, Missale C, Caron MG. Anterior pituitary hypoplasia and dwarsm in mice lacking the dopamine transporter. Neuron 19: 127138, 1997. Bradford AP, Conrad KE, Tran PH, Ostrowski MC, GutierrezHartmann A. GHF-1/Pit-1 functions as a cell-specic integrator of Ras signaling by targeting the Ras pathway to a composite Ets-1/ GHF-1 response element. J Biol Chem 271: 24639 24648, 1996. Bradford AP, Conrad KE, Wasylyk C, Wasylyk B, GutierrezHartmann A. Functional interaction of c-Ets-1 and GHF-1/Pit-1 mediates Ras activation of pituitary-specic gene expression: mapping of the essential c-Ets-1 domain. Mol Cell Biol 15: 2849 2857, 1995. Bradford AP, Wasylyk C, Wasylyk B, Gutierrez-Hartmann A. Interaction of Ets-1 and the POU-homeodomain protein GHF-1/ Pit-1 reconstitutes pituitary-specic gene expression. Mol Cell Biol 17: 10651074, 1997. Briata P, Ilengo C, Corte G, Moroni C, Rosenfeld MG, Chen CY, Gherzi R. The Wnt/beta-catenin3 Pitx2 pathway controls the turnover of Pitx2 and other unstable mRNAs. Mol Cell 12: 1201 1211, 2003. Brickman JM, Clements M, Tyrell R, McNay D, Woods K, Warner J, Stewart A, Beddington RS, Dattani M. Molecular effects of novel mutations in Hesx1/HESX1 associated with human pituitary disorders. Development 128: 5189 5199, 2001. Brinkmeier ML, Gordon DF, Dowding JM, Saunders TL, Kendall SK, Sarapura VD, Wood WM, Ridgway EC, Camper SA. Cell-specic expression of the mouse glycoprotein hormone alphasubunit gene requires multiple interacting DNA elements in transgenic mice and cultured cells. Mol Endocrinol 12: 622 633, 1998. Brinkmeier ML, Potok MA, Cha KB, Gridley T, Stifani S, Meeldijk J, Clevers H, Camper SA. TCF and Groucho-related www.prv.org
87 JULY 2007
956
ZHU, GLEIBERMAN, AND ROSENFELD genes inuence pituitary growth and development. Mol Endocrinol 17: 21522161, 2003. Brugmann SA, Pandur PD, Kenyon KL, Pignoni F, Moody SA. Six1 promotes a placodal fate within the lateral neurogenic ectoderm by functioning as both a transcriptional activator and repressor. Development 131: 58715881, 2004. Burger LL, Haisenleder DJ, Dalkin AC, Marshall JC. Regulation of gonadotropin subunit gene transcription. J Mol Endocrinol 33: 559 584, 2004. Cabanillas AM, Smith GE, Darling DS. T3-activation of the rat growth hormone gene is inhibited by a zinc nger/homeodomain protein. Mol Cell Endocrinol 181: 131137, 2001. Cai CL, Liang X, Shi Y, Chu PH, Pfaff SL, Chen J, Evans S. Isl1 identies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell 5: 877 889, 2003. Cajiao I, Zhang A, Yoo EJ, Cooke NE, Liebhaber SA. Bystander gene activation by a locus control region. EMBO J 23: 3854 3863, 2004. Camper SA, Saunders TL, Katz RW, Reeves RH. The Pit-1 transcription factor gene is a candidate for the murine Snell dwarf mutation. Genomics 8: 586 590, 1990. Cariboni A, Pimpinelli F, Colamarino S, Zaninetti R, Piccolella M, Rumio C, Piva F, Rugarli EI, Maggi R. The product of X-linked Kallmanns syndrome gene (KAL1) affects the migratory activity of gonadotropin-releasing hormone (GnRH)-producing neurons. Hum Mol Genet 13: 27812791, 2004. Carvalho LR, Woods KS, Mendonca BB, Marcal N, Zamparini AL, Stifani S, Brickman JM, Arnhold IJ, Dattani MT. A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction. J Clin Invest 112: 11921201, 2003. Cattanach BM, Iddon CA, Charlton HM, Chiappa SA, Fink G. Gonadotrophin-releasing hormone deciency in a mutant mouse with hypogonadism. Nature 269: 338 340, 1977. Celli G, LaRochelle WJ, Mackem S, Sharp R, Merlino G. Soluble dominant-negative receptor uncovers essential roles for broblast growth factors in multi-organ induction and patterning. EMBO J 17: 16421655, 1998. Cha KB, Douglas KR, Potok MA, Liang H, Jones SN, Camper SA. WNT5A signaling affects pituitary gland shape. Mech Dev 121: 183194, 2004. Charles MA, Saunders TL, Wood WM, Owens K, Parlow AF, Camper SA, Ridgway EC, Gordon DF. Pituitary-specic Gata2 knockout: effects on gonadotrope and thyrotrope function. Mol Endocrinol 20: 1366 1377, 2006. Charles MA, Suh H, Hjalt TA, Drouin J, Camper SA, Gage PJ. PITX genes are required for cell survival and Lhx3 activation. Mol Endocrinol 19: 18931903, 2005. Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, Westphal H, Beachy PA. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383: 407 413, 1996. Cohen LE, Hashimoto Y, Zanger K, Wondisford F, Radovick S. CREB-independent regulation by CBP is a novel mechanism of human growth hormone gene expression. J Clin Invest 104: 1123 1130, 1999. Cohen LE, Radovick S. Other transcription factors and hypopituitarism. Rev Endocr Metab Disorders 3: 301311, 2002. Coletta RD, Christensen K, Reichenberger KJ, Lamb J, Micomonaco D, Huang L, Wolf DM, Muller-Tidow C, Golub TR, Kawakami K, Ford HL. The Six1 homeoprotein stimulates tumorigenesis by reactivation of cyclin A1. Proc Natl Acad Sci USA 101: 6478 6483, 2004. Corradi A, Croci L, Broccoli V, Zecchini S, Previtali S, Wurst W, Amadio S, Maggi R, Quattrini A, Consalez GG. Hypogonadotropic hypogonadism and peripheral neuropathy in Ebf2-null mice. Development 130: 401 410, 2003. Coss D, Jacobs SB, Bender CE, Mellon PL. A novel AP-1 site is critical for maximal induction of the follicle-stimulating hormone beta gene by gonadotropin-releasing hormone. J Biol Chem 279: 152162, 2004. Physiol Rev VOL 50. Couly G, Le Douarin NM. The fate map of the cephalic neural primordium at the presomitic to the 3-somite stage in the avian embryo. Development 103 Suppl: 101113, 1988. 51. Couly GF, Le Douarin NM. Mapping of the early neural primordium in quail-chick chimeras. II. The prosencephalic neural plate and neural folds: implications for the genesis of cephalic human congenital abnormalities. Dev Biol 120: 198 214, 1987. 52. Crenshaw EB 3rd, Kalla K, Simmons DM, Swanson LW, Rosenfeld MG. Cell-specic expression of the prolactin gene in transgenic mice is controlled by synergistic interactions between promoter and enhancer elements. Genes Dev 3: 959 972, 1989. 53. Cushman LJ, Showalter AD, Rhodes SJ. Genetic defects in the development and function of the anterior pituitary gland. Ann Med 34: 179 191, 2002. 54. Cushman LJ, Watkins-Chow DE, Brinkmeier ML, Raetzman LT, Radak AL, Lloyd RV, Camper SA. Persistent Prop1 expression delays gonadotrope differentiation and enhances pituitary tumor susceptibility. Hum Mol Genet 10: 11411153, 2001. 55. Daikoku S, Chikamori M, Adachi T, Maki Y. Effect of the basal diencephalon on the development of Rathkes pouch in rats: a study in combined organ cultures. Dev Biol 90: 198 202, 1982. 56. Dasen JS, Barbera JP, Herman TS, Connell SO, Olson L, Ju B, Tollkuhn J, Baek SH, Rose DW, Rosenfeld MG. Temporal regulation of a paired-like homeodomain repressor/TLE corepressor complex and a related activator is required for pituitary organogenesis. Genes Dev 15: 31933207, 2001. 57. Dasen JS, OConnell SM, Flynn SE, Treier M, Gleiberman AS, Szeto DP, Hooshmand F, Aggarwal AK, Rosenfeld MG. Reciprocal interactions of Pit1 and GATA2 mediate signaling gradientinduced determination of pituitary cell types. Cell 97: 587598, 1999. 58. Dasen JS, Rosenfeld MG. Signaling and transcriptional mechanisms in pituitary development. Annu Rev Neurosci 24: 327355, 2001. 59. Dattani MT, Martinez-Barbera JP, Thomas PQ, Brickman JM, Gupta R, Martensson IL, Toresson H, Fox M, Wales JK, Hindmarsh PC, Krauss S, Beddington RS, Robinson IC. Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet 19: 125133, 1998. 60. Day RN, Koike S, Sakai M, Muramatsu M, Maurer RA. Both Pit-1 and the estrogen receptor are required for estrogen responsiveness of the rat prolactin gene. Mol Endocrinol 4: 1964 1971, 1990. 61. Day RN, Liu J, Sundmark V, Kawecki M, Berry D, Elsholtz HP. Selective inhibition of prolactin gene transcription by the ETS-2 repressor factor. J Biol Chem 273: 31909 31915, 1998. 62. Day RN, Voss TC, Enwright JF 3rd, Booker CF, Periasamy A, Schaufele F. Imaging the localized protein interactions between Pit-1 and the CCAAT/enhancer binding protein alpha in the living pituitary cell nucleus. Mol Endocrinol 17: 333345, 2003. 63. De Souza FS, Santangelo AM, Bumaschny V, Avale ME, Smart JL, Low MJ, Rubinstein M. Identication of neuronal enhancers of the proopiomelanocortin gene by transgenic mouse analysis and phylogenetic footprinting. Mol Cell Biol 25: 3076 3086, 2005. 64. Del Bene F, Tessmar-Raible K, Wittbrodt J. Direct interaction of geminin and Six3 in eye development. Nature 427: 745749, 2004. 65. Dellovade TL, Pfaff DW, Schwanzel-Fukuda M. The gonadotropin-releasing hormone system does not develop in Small-Eye (Sey) mouse phenotype. Brain Res 107: 233240, 1998. 66. DiMattia GE, Rhodes SJ, Krones A, Carriere C, OConnell S, Kalla K, Arias C, Sawchenko P, Rosenfeld MG. The Pit-1 gene is regulated by distinct early and late pituitary-specic enhancers. Dev Biol 182: 180 190, 1997. 67. Dode C, Hardelin JP. Kallmann syndrome: broblast growth factor signaling insufciency? J Mol Med 82: 725734, 2004. 68. Dorn C, Ou Q, Svaren J, Crawford PA, Sadovsky Y. Activation of luteinizing hormone beta gene by gonadotropin-releasing hormone requires the synergy of early growth response-1 and steroidogenic factor-1. J Biol Chem 274: 13870 13876, 1999. 69. Douglas KR, Brinkmeier ML, Kennell JA, Eswara P, Harrison TA, Patrianakos AI, Sprecher BS, Potok MA, Lyons RH Jr, MacDougald OA, Camper SA. Identication of members of the www.prv.org
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46. 47.
48.
49.
87 JULY 2007
MOLECULAR PHYSIOLOGY OF PITUITARY DEVELOPMENT Wnt signaling pathway in the embryonic pituitary gland. Mamm Genome 12: 843 851, 2001. Drolet DW, Scully KM, Simmons DM, Wegner M, Chu KT, Swanson LW, Rosenfeld MG. TEF, a transcription factor expressed specically in the anterior pituitary during embryogenesis, denes a new class of leucine zipper proteins. Genes Dev 5: 1739 1753, 1991. Duval DL, Jean A, Gutierrez-Hartmann A. Ras signaling and transcriptional synergy at a exible Ets-1/Pit-1 composite DNA element is dened by the assembly of selective activation domains. J Biol Chem 278: 39684 39696, 2003. Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA, McMahon AP. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75: 14171430, 1993. Elchebly M, Wagner J, Kennedy TE, Lanctot C, Michaliszyn E, Itie A, Drouin J, Tremblay ML. Neuroendocrine dysplasia in mice lacking protein tyrosine phosphatase sigma. Nat Genet 21: 330 333, 1999. Enwright JF 3rd, Kawecki-Crook MA, Voss TC, Schaufele F, Day RN. A PIT-1 homeodomain mutant blocks the intranuclear recruitment of the CCAAT/enhancer binding protein alpha required for prolactin gene transcription. Mol Endocrinol 17: 209 222, 2003. Ericson J, Norlin S, Jessell TM, Edlund T. Integrated FGF and BMP signaling controls the progression of progenitor cell differentiation and the emergence of pattern in the embryonic anterior pituitary. Development 125: 10051015, 1998. Fedtsova N, Perris R, Turner EE. Sonic hedgehog regulates the position of the trigeminal ganglia. Dev Biol 261: 456 469, 2003. Fedtsova N, Turner EE. Signals from the ventral midline and isthmus regulate the development of Brn3.0-expressing neurons in the midbrain. Mech Dev 105: 129 144, 2001. Fedtsova NG, Barabanov VM. [Lenticular and adenohypophyseal differentiation in the oral region ectoderm of chick embryos in tissue culture.] Ontogenez 9: 609 615, 1978. Fedtsova NG, Barabanov VM. [The distribution of competence for adenohypophysis development in the ectoderm of chick embryos.] Ontogenez 21: 254 260, 1990. Ferrand R, Fremont PH, Dubois MP. Immunocytological study on the differentiation of chick and quail adenohypophysis epithelial rudiments, grafted or cultivated in vitro: evidence for polypeptidic hormones. Am J Anat 158: 411 431, 1980. Ferrand R, Pearse AG, Polak JM, Le Douarin NM. Immunohistochemical studies on the development of avian embryo pituitary corticotrophs under normal and experimental conditions. Histochemie 38: 133141, 1974. Forrest D, Erway LC, Ng L, Altschuler R, Curran T. Thyroid hormone receptor beta is essential for development of auditory function. Nat Genet 13: 354 357, 1996. Fremont PH, Ferrand R. In vitro studies on the self-differentiating capacities of quail adenohypophysis epithelium. Anat Embryol 156: 255267, 1979. Fremont PH, Ferrand R. The differentiation of follicular-like cells from the epithelium of Rathkes pouch grown in vitro. Anat Embryol 160: 275284, 1980. Gachon F, Fonjallaz P, Damiola F, Gos P, Kodama T, Zakany J, Duboule D, Petit B, Tafti M, Schibler U. The loss of circadian PAR bZip transcription factors results in epilepsy. Genes Dev 18: 13971412, 2004. Gage PJ, Brinkmeier ML, Scarlett LM, Knapp LT, Camper SA, Mahon KA. The Ames dwarf gene, df, is required early in pituitary ontogeny for the extinction of Rpx transcription and initiation of lineage-specic cell proliferation. Mol Endocrinol 10: 1570 1581, 1996. Gage PJ, Lossie AC, Scarlett LM, Lloyd RV, Camper SA. Ames dwarf mice exhibit somatotrope commitment but lack growth hormone-releasing factor response. Endocrinology 136: 11611167, 1995. Gage PJ, Suh H, Camper SA. Dosage requirement of Pitx2 for development of multiple organs. Development 126: 4643 4651, 1999. Gage PJ, Suh H, Camper SA. The bicoid-related Pitx gene family in development. Mamm Genome 10: 197200, 1999. Physiol Rev VOL
957
70.
71.
72.
73.
74.
75.
76. 77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90. Gestri G, Carl M, Appolloni I, Wilson SW, Barsacchi G, Andreazzoli M. Six3 functions in anterior neural plate specication by promoting cell proliferation and inhibiting Bmp4 expression. Development 132: 24012413, 2005. 91. Glasgow E, Karavanov AA, Dawid IB. Neuronal and neuroendocrine expression of lim3, a LIM class homeobox gene, is altered in mutant zebrash with axial signaling defects. Dev Biol 192: 405 419, 1997. 92. Gleiberman AS, Fedtsova NG, Rosenfeld MG. Tissue interactions in the induction of anterior pituitary: role of the ventral diencephalon, mesenchyme, notochord. Dev Biol 213: 340 353, 1999. 93. Godfrey P, Rahal JO, Beamer WG, Copeland NG, Jenkins NA, Mayo KE. GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor function. Nat Genet 4: 227232, 1993. 94. Good DJ, Porter FD, Mahon KA, Parlow AF, Westphal H, Kirsch IR. Hypogonadism and obesity in mice with a targeted deletion of the Nhlh2 gene. Nat Genet 15: 397 401, 1997. 95. Gordon DF, Lewis SR, Haugen BR, James RA, McDermott MT, Wood WM, Ridgway EC. Pit-1 and GATA-2 interact and functionally cooperate to activate the thyrotropin beta-subunit promoter. J Biol Chem 272: 24339 24347, 1997. 96. Goshu E, Jin H, Lovejoy J, Marion JF, Michaud JL, Fan CM. Sim2 contributes to neuroendocrine hormone gene expression in the anterior hypothalamus. Mol Endocrinol 18: 12511262, 2004. 97. Gothe S, Wang Z, Ng L, Kindblom JM, Barros AC, Ohlsson C, Vennstrom B, Forrest D. Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitarythyroid axis, growth, bone maturation. Genes Dev 13: 1329 1341, 1999. 98. Gregory SJ, Lacza CT, Detz AA, Xu S, Petrillo LA, Kaiser UB. Synergy between activin A and gonadotropin-releasing hormone in transcriptional activation of the rat follicle-stimulating hormonebeta gene. Mol Endocrinol 19: 237254, 2005. 99. Grifone R, Demignon J, Houbron C, Souil E, Niro C, Seller MJ, Hamard G, Maire P. Six1 and Six4 homeoproteins are required for Pax3 and Mrf expression during myogenesis in the mouse embryo. Development 132: 22352249, 2005. 100. Halvorson LM, Ito M, Jameson JL, Chin WW. Steroidogenic factor-1 and early growth response protein 1 act through two composite DNA binding sites to regulate luteinizing hormone betasubunit gene expression. J Biol Chem 273: 1471214720, 1998. 101. Halvorson LM, Kaiser UB, Chin WW. Stimulation of luteinizing hormone beta gene promoter activity by the orphan nuclear receptor, steroidogenic factor-1. J Biol Chem 271: 6645 6650, 1996. 102. Halvorson LM, Kaiser UB, Chin WW. The protein kinase C system acts through the early growth response protein 1 to increase LHbeta gene expression in synergy with steroidogenic factor-1. Mol Endocrinol 13: 106 116, 1999. 103. Hammer GD, Fairchild-Huntress V, Low MJ. Pituitary-specic and hormonally regulated gene expression directed by the rat proopiomelanocortin promoter in transgenic mice. Mol Endocrinol 4: 1689 1697, 1990. 104. Hashimoto K, Yamada M, Monden T, Satoh T, Wondisford FE, Mori M. Thyrotropin-releasing hormone (TRH) specic interaction between amino terminus of P-Lim and CREB binding protein (CBP). Mol Cell Endocrinol 229: 1120, 2005. 105. Hashimoto K, Zanger K, Hollenberg AN, Cohen LE, Radovick S, Wondisford FE. cAMP response element-binding protein-binding protein mediates thyrotropin-releasing hormone signaling on thyrotropin subunit genes. J Biol Chem 275: 3336533372, 2000. 106. Heanue TA, Reshef R, Davis RJ, Mardon G, Oliver G, Tomarev S, Lassar AB, Tabin CJ. Synergistic regulation of vertebrate muscle development by Dach2, Eya2, Six1, homologs of genes required for Drosophila eye formation. Genes Dev 13: 32313243, 1999. 107. Hebert JM, Lin M, Partanen J, Rossant J, McConnell SK. FGF signaling through FGFR1 is required for olfactory bulb morphogenesis. Development 130: 11011111, 2003. 108. Hermesz E, Mackem S, Mahon KA. Rpx: a novel anterior-restricted homeobox gene progressively activated in the prechordal www.prv.org
87 JULY 2007
958
ZHU, GLEIBERMAN, AND ROSENFELD plate, anterior neural plate and Rathkes pouch of the mouse embryo. Development 122: 4152, 1996. Hermesz E, Williams-Simons L, Mahon KA. A novel inducible element, activated by contact with Rathkes pouch, is present in the regulatory region of the Rpx/Hesx1 homeobox gene. Dev Biol 260: 68 78, 2003. Herzog W, Sonntag C, Walderich B, Odenthal J, Maischein HM, Hammerschmidt M. Genetic analysis of adenohypophysis formation in zebrash. Mol Endocrinol 18: 11851195, 2004. Herzog W, Zeng X, Lele Z, Sonntag C, Ting JW, Chang CY, Hammerschmidt M. Adenohypophysis formation in the zebrash and its dependence on sonic hedgehog. Dev Biol 254: 36 49, 2003. Ho Y, Elefant F, Cooke N, Liebhaber S. A dened locus control region determinant links chromatin domain acetylation with longrange gene activation. Mol Cell 9: 291302, 2002. Ho Y, Elefant F, Liebhaber SA, Cooke NE. Locus control region transcription plays an active role in long-range gene activation. Mol Cell 23: 365375, 2006. Hogan BL, Horsburgh G, Cohen J, Hetherington CM, Fisher G, Lyon MF. Small eyes (Sey): a homozygous lethal mutation on chromosome 2 which affects the differentiation of both lens and nasal placodes in the mouse. J Embryol Exp Morphol 97: 95110, 1986. Hosoya T, Oda Y, Takahashi S, Morita M, Kawauchi S, Ema M, Yamamoto M, Fujii-Kuriyama Y. Defective development of secretory neurones in the hypothalamus of Arnt2-knockout mice. Genes Cells 6: 361374, 2001. Howard PW, Maurer RA. A composite Ets/Pit-1 binding site in the prolactin gene can mediate transcriptional responses to multiple signal transduction pathways. J Biol Chem 270: 20930 20936, 1995. Hui CC, Slusarski D, Platt KA, Holmgren R, Joyner AL. Expression of three mouse homologs of the Drosophila segment polarity gene cubitus interruptus, Gli, Gli-2, Gli-3, in ectoderm- and mesoderm-derived tissues suggests multiple roles during postimplantation development. Dev Biol 162: 402 413, 1994. Hunter CS, Rhodes SJ. LIM-homeodomain genes in mammalian development and human disease. Mol Biol Rep 32: 6777, 2005. Ikeda Y, Luo X, Abbud R, Nilson JH, Parker KL. The nuclear receptor steroidogenic factor 1 is essential for the formation of the ventromedial hypothalamic nucleus. Mol Endocrinol 9: 478 486, 1995. Ingraham HA, Lala DS, Ikeda Y, Luo X, Shen WH, Nachtigal MW, Abbud R, Nilson JH, Parker KL. The nuclear receptor steroidogenic factor 1 acts at multiple levels of the reproductive axis. Genes Dev 8: 23022312, 1994. Jackson SM, Gutierrez-Hartmann A, Hoefer JP. Upstream stimulatory factor, a basic-helix-loop-helix-zipper protein, regulates the activity of the alpha-glycoprotein hormone subunit gene in pituitary cells. Mol Endocrinol 9: 278 291, 1995. Jacob KK, Stanley FM. CCAAT/enhancer-binding protein alpha is a physiological regulator of prolactin gene expression. Endocrinology 140: 4542 4550, 1999. Jacobs SB, Coss D, McGillivray SM, Mellon PL. Nuclear factor Y and steroidogenic factor 1 physically and functionally interact to contribute to cell-specic expression of the mouse follicle-stimulating hormone-beta gene. Mol Endocrinol 17: 1470 1483, 2003. Japon MA, Rubinstein M, Low MJ. In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development. J Histochem Cytochem 42: 11171125, 1994. Jiang Q, Jeong KH, Horton CD, Halvorson LM. Pituitary homeobox 1 (Pitx1) stimulates rat LHbeta gene expression via two functional DNA-regulatory regions. J Mol Endocrinol 35: 145158, 2005. Jing E, Nillni EA, Sanchez VC, Stuart RC, Good DJ. Deletion of the Nhlh2 transcription factor decreases the levels of the anorexigenic peptides alpha melanocyte-stimulating hormone and thyrotropin-releasing hormone and implicates prohormone convertases I and II in obesity. Endocrinology 145: 15031513, 2004. Jones BK, Monks BR, Liebhaber SA, Cooke NE. The human growth hormone gene is regulated by a multicomponent locus control region. Mol Cell Biol 15: 7010 7021, 1995. Jorgensen JS, Quirk CC, Nilson JH. Multiple and overlapping combinatorial codes orchestrate hormonal responsiveness and dicPhysiol Rev VOL tate cell-specic expression of the genes encoding luteinizing hormone. Endocr Rev 25: 521542, 2004. Kaiser UB, Halvorson LM, Chen MT. Sp1, steroidogenic factor 1 (SF-1), early growth response protein 1 (egr-1) binding sites form a tripartite gonadotropin-releasing hormone response element in the rat luteinizing hormone-beta gene promoter: an integral role for SF-1. Mol Endocrinol 14: 12351245, 2000. Kaiser UB, Sabbagh E, Chen MT, Chin WW, Saunders BD. Sp1 binds to the rat luteinizing hormone beta (LHbeta) gene promoter and mediates gonadotropin-releasing hormone-stimulated expression of the LHbeta subunit gene. J Biol Chem 273: 1294312951, 1998. Kapsimali M, Caneparo L, Houart C, Wilson SW. Inhibition of Wnt/Axin/beta-catenin pathway activity promotes ventral CNS midline tissue to adopt hypothalamic rather than oorplate identity. Development 131: 59235933, 2004. Kawakami K, Sato S, Ozaki H, Ikeda K. Six family genes structure and function as transcription factors and their roles in development. Bioessays 22: 616 626, 2000. Kawamura K, Kikuyama S. Induction from posterior hypothalamus is essential for the development of the pituitary proopiomelacortin (POMC) cells of the toad (Bufo japonicus). Cell Tissue Res 279: 233239, 1995. Kawamura K, Kikuyama S. Morphogenesis of the hypothalamus and hypophysis: their association, dissociation and reassociation before and after Rathke. Arch Histol Cytol 61: 189 198, 1998. Kawamura K, Kouki T, Kawahara G, Kikuyama S. Hypophyseal development in vertebrates from amphibians to mammals. Gen Comp Endocrinol 126: 130 135, 2002. Keegan CE, Camper SA. Mouse knockout solves endocrine puzzle and promotes new pituitary lineage model. Genes Dev 17: 677 682, 2003. Keith B, Adelman DM, Simon MC. Targeted mutation of the murine arylhydrocarbon receptor nuclear translocator 2 (Arnt2) gene reveals partial redundancy with Arnt. Proc Natl Acad Sci USA 98: 6692 6697, 2001. Kelberman D, Rizzoti K, Avilion A, Bitner-Glindzicz M, Cianfarani S, Collins J, Chong WK, Kirk JM, Achermann JC, Ross R, Carmignac D, Lovell-Badge R, Robinson IC, Dattani MT. Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans. J Clin Invest 116: 24422455, 2006. Kelly MA, Rubinstein M, Asa SL, Zhang G, Saez C, Bunzow JR, Allen RG, Hnasko R, Ben-Jonathan N, Grandy DK, Low MJ. Pituitary lactotroph hyperplasia and chronic hyperprolactinemia in dopamine D2 receptor-decient mice. Neuron 19: 103113, 1997. Kendall SK, Gordon DF, Birkmeier TS, Petrey D, Sarapura VD, OShea KS, Wood WM, Lloyd RV, Ridgway EC, Camper SA. Enhancer-mediated high level expression of mouse pituitary glycoprotein hormone alpha-subunit transgene in thyrotropes, gonadotropes, developing pituitary gland. Mol Endocrinol 8: 1420 1433, 1994. Kendall SK, Saunders TL, Jin L, Lloyd RV, Glode LM, Nett TM, Keri RA, Nilson JH, Camper SA. Targeted ablation of pituitary gonadotropes in transgenic mice. Mol Endocrinol 5: 2025 2036, 1991. Keri RA, Bachmann DJ, Behrooz A, Herr BD, Ameduri RK, Quirk CC, Nilson JH. An NF-Y binding site is important for basal, but not gonadotropin-releasing hormone-stimulated, expression of the luteinizing hormone beta subunit gene. J Biol Chem 275: 13082 13088, 2000. Keri RA, Nilson JH. A steroidogenic factor-1 binding site is required for activity of the luteinizing hormone beta subunit promoter in gonadotropes of transgenic mice. J Biol Chem 271: 10782 10785, 1996. Keri RA, Wolfe MW, Saunders TL, Anderson I, Kendall SK, Wagner T, Yeung J, Gorski J, Nett TM, Camper SA, Nilson JH. The proximal promoter of the bovine luteinizing hormone betasubunit gene confers gonadotrope-specic expression and regulation by gonadotropin-releasing hormone, testosterone, 17 betaestradiol in transgenic mice. Mol Endocrinol 8: 18071816, 1994. Kimura S, Hara Y, Pineau T, Fernandez-Salguero P, Fox CH, Ward JM, Gonzalez FJ. The T/ebp null mouse: thyroid-specic www.prv.org
109.
129.
110.
130.
111.
112.
131.
113.
132.
114.
133.
115.
134.
135.
116.
136.
117.
137.
118. 119.
138.
120.
139.
121.
140.
122.
123.
141.
124.
142.
125.
143.
126.
144.
127.
128.
145.
87 JULY 2007
MOLECULAR PHYSIOLOGY OF PITUITARY DEVELOPMENT enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, pituitary. Genes Dev 10: 60 69, 1996. Kioussi C, Briata P, Baek SH, Rose DW, Hamblet NS, Herman T, Ohgi KA, Lin C, Gleiberman A, Wang J, Brault V, RuizLozano P, Nguyen HD, Kemler R, Glass CK, Wynshaw-Boris A, Rosenfeld MG. Identication of a Wnt/Dvl/beta-Catenin3 Pitx2 pathway mediating cell-type-specic proliferation during development. Cell 111: 673 685, 2002. Kioussi C, OConnell S, St-Onge L, Treier M, Gleiberman AS, Gruss P, Rosenfeld MG. Pax6 is essential for establishing ventraldorsal cell boundaries in pituitary gland development. Proc Natl Acad Sci USA 96: 14378 14382, 1999. Kitamura K, Miura H, Miyagawa-Tomita S, Yanazawa M, Katoh-Fukui Y, Suzuki R, Ohuchi H, Suehiro A, Motegi Y, Nakahara Y, Kondo S, Yokoyama M. Mouse Pitx2 deciency leads to anomalies of the ventral body wall, heart, extra- and periocular mesoderm and right pulmonary isomerism. Development 126: 5749 5758, 1999. Kondoh H, Uchikawa M, Yoda H, Takeda H, Furutani-Seiki M, Karlstrom RO. Zebrash mutations in Gli-mediated hedgehog signaling lead to lens transdifferentiation from the adenohypophysis anlage. Mech Dev 96: 165174, 2000. Kouki T, Imai H, Aoto K, Eto K, Shioda S, Kawamura K, Kikuyama S. Developmental origin of the rat adenohypophysis prior to the formation of Rathkes pouch. Development 128: 959 963, 2001. Kruger M, Braun T. The neuronal basic helix-loop-helix transcription factor NSCL-1 is dispensable for normal neuronal development. Mol Cell Biol 22: 792 800, 2002. Kruger M, Ruschke K, Braun T. NSCL-1 and NSCL-2 synergistically determine the fate of GnRH-1 neurons and control necdin gene expression. EMBO J 23: 4353 4364, 2004. Krylova IN, Sablin EP, Moore J, Xu RX, Waitt GM, MacKay JA, Juzumiene D, Bynum JM, Madauss K, Montana V, Lebedeva L, Suzawa M, Williams JD, Williams SP, Guy RK, Thornton JW, Fletterick RJ, Willson TM, Ingraham HA. Structural analyses reveal phosphatidylinositols as ligands for the NR5 orphan receptors SF-1 and LRH-1. Cell 120: 343355, 2005. Laclef C, Hamard G, Demignon J, Souil E, Houbron C, Maire P. Altered myogenesis in Six1-decient mice. Development 130: 2239 2252, 2003. Laclef C, Souil E, Demignon J, Maire P. Thymus, kidney and craniofacial abnormalities in Six 1 decient mice. Mech Dev 120: 669 679, 2003. Lagutin OV, Zhu CC, Kobayashi D, Topczewski J, Shimamura K, Puelles L, Russell HR, McKinnon PJ, Solnica-Krezel L, Oliver G. Six3 repression of Wnt signaling in the anterior neuroectoderm is essential for vertebrate forebrain development. Genes Dev 17: 368 379, 2003. Lamolet B, Poulin G, Chu K, Guillemot F, Tsai MJ, Drouin J. Tpit-independent function of NeuroD1(BETA2) in pituitary corticotroph differentiation. Mol Endocrinol 18: 9951003, 2004. Lamolet B, Pulichino AM, Lamonerie T, Gauthier Y, Brue T, Enjalbert A, Drouin J. A pituitary cell-restricted T box factor, Tpit, activates POMC transcription in cooperation with Pitx homeoproteins. Cell 104: 849 859, 2001. Lamonerie T, Tremblay JJ, Lanctot C, Therrien M, Gauthier Y, Drouin J. Ptx1, a bicoid-related homeo box transcription factor involved in transcription of the pro-opiomelanocortin gene. Genes Dev 10: 1284 1295, 1996. Lanctot C, Moreau A, Chamberland M, Tremblay ML, Drouin J. Hindlimb patterning and mandible development require the Ptx1 gene. Development 126: 18051810, 1999. Laumonnier F, Ronce N, Hamel BC, Thomas P, Lespinasse J, Raynaud M, Paringaux C, Van Bokhoven H, Kalscheuer V, Fryns JP, Chelly J, Moraine C, Briault S. Transcription factor SOX3 is involved in X-linked mental retardation with growth hormone deciency. Am J Hum Genet 71: 1450 1455, 2002. Lawson KA, Dunn NR, Roelen BA, Zeinstra LM, Davis AM, Wright CV, Korving JP, Hogan BL. Bmp4 is required for the generation of primordial germ cells in the mouse embryo. Genes Dev 13: 424 436, 1999. Physiol Rev VOL
959
146.
147.
148.
149.
150.
151.
152.
153.
154.
155.
156.
157.
158.
159.
160.
161.
162.
163. Lee SL, Sadovsky Y, Swirnoff AH, Polish JA, Goda P, Gavrilina G, Milbrandt J. Luteinizing hormone deciency and female infertility in mice lacking the transcription factor NGFI-A (Egr-1). Science 273: 1219 1221, 1996. 164. Li H, Zeitler PS, Valerius MT, Small K, Potter SS. Gsh-1, an orphan Hox gene, is required for normal pituitary development. EMBO J 15: 714 724, 1996. 165. Li P, He X, Gerrero MR, Mok M, Aggarwal A, Rosenfeld MG. Spacing and orientation of bipartite DNA-binding motifs as potential functional determinants for POU domain factors. Genes Dev 7: 24832496, 1993. 166. Li S, Crenshaw EB, 3rd Rawson EJ, Simmons DM, Swanson LW, Rosenfeld MG. Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. Nature 347: 528 533, 1990. 167. Li X, Oghi KA, Zhang J, Krones A, Bush KT, Glass CK, Nigam SK, Aggarwal AK, Maas R, Rose DW, Rosenfeld MG. Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature 426: 247254, 2003. 168. Li X, Perissi V, Liu F, Rose DW, Rosenfeld MG. Tissue-specic regulation of retinal and pituitary precursor cell proliferation. Science 297: 1180 1183, 2002. 169. Li Y, Choi M, Cavey G, Daugherty J, Suino K, Kovach A, Bingham NC, Kliewer SA, Xu HE. Crystallographic identication and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor-1. Mol Cell 17: 491 502, 2005. 170. Lin CR, Kioussi C, OConnell S, Briata P, Szeto D, Liu F, Izpisua-Belmonte JC, Rosenfeld MG. Pitx2 regulates lung asymmetry, cardiac positioning and pituitary and tooth morphogenesis. Nature 401: 279 282, 1999. 171. Lin SC, Li S, Drolet DW, Rosenfeld MG. Pituitary ontogeny of the Snell dwarf mouse reveals Pit-1-independent and Pit-1-dependent origins of the thyrotrope. Development 120: 515522, 1994. 172. Lin SC, Lin CR, Gukovsky I, Lusis AJ, Sawchenko PE, Rosenfeld MG. Molecular basis of the little mouse phenotype and implications for cell type-specic growth. Nature 364: 208 213, 1993. 173. Lira SA, Crenshaw EB, 3rd Glass CK, Swanson LW, Rosenfeld MG. Identication of rat growth hormone genomic sequences targeting pituitary expression in transgenic mice. Proc Natl Acad Sci USA 85: 4755 4759, 1988. 174. Liu B, Hammer GD, Rubinstein M, Mortrud M, Low MJ. Identication of DNA elements cooperatively activating proopiomelanocortin gene expression in the pituitary glands of transgenic mice. Mol Cell Biol 12: 3978 3990, 1992. 175. Liu B, Mortrud M, Low MJ. DNA elements with AT-rich core sequences direct pituitary cell-specic expression of the pro-opiomelanocortin gene in transgenic mice. Biochem J 312: 827 832, 1995. 176. Liu J, Lin C, Gleiberman A, Ohgi KA, Herman T, Huang HP, Tsai MJ, Rosenfeld MG. Tbx19, a tissue-selective regulator of POMC gene expression. Proc Natl Acad Sci USA 98: 8674 8679, 2001. 177. Liu JC, Baker RE, Chow W, Sun CK, Elsholtz HP. Epigenetic mechanisms in the dopamine D2 receptor-dependent inhibition of the prolactin gene. Mol Endocrinol 19: 1904 1917, 2005. 178. Liu JC, Baker RE, Sun C, Sundmark VC, Elsholtz HP. Activation of Go-coupled dopamine D2 receptors inhibits ERK1/ERK2 in pituitary cells. A key step in the transcriptional suppression of the prolactin gene. J Biol Chem 277: 35819 35825, 2002. 179. Liu NA, Huang H, Yang Z, Herzog W, Hammerschmidt M, Lin S, Melmed S. Pituitary corticotroph ontogeny and regulation in transgenic zebrash. Mol Endocrinol 17: 959 966, 2003. 180. Liu NA, Liu Q, Wawrowsky K, Yang Z, Lin S, Melmed S. Prolactin receptor signaling mediates the osmotic response of embryonic zebrash lactotrophs. Mol Endocrinol 20: 871 880, 2006. 181. Lu MF, Pressman C, Dyer R, Johnson RL, Martin JF. Function of Rieger syndrome gene in left-right asymmetry and craniofacial development. Nature 401: 276 278, 1999. 182. Luo L, Yang X, Takihara Y, Knoetgen H, Kessel M. The cellcycle regulator geminin inhibits Hox function through direct and polycomb-mediated interactions. Nature 427: 749 753, 2004. www.prv.org
87 JULY 2007
960
ZHU, GLEIBERMAN, AND ROSENFELD itor cells in the developing anterior pituitary. Mech Dev 96: 175182, 2000. Nowakowski BE, Maurer RA. Multiple Pit-1-binding sites facilitate estrogen responsiveness of the prolactin gene. Mol Endocrinol 8: 17421749, 1994. Ohto H, Kamada S, Tago K, Tominaga SI, Ozaki H, Sato S, Kawakami K. Cooperation of six and eya in activation of their target genes through nuclear translocation of Eya. Mol Cell Biol 19: 6815 6824, 1999. Ohuchi H, Hori Y, Yamasaki M, Harada H, Sekine K, Kato S, Itoh N. FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multi-organ development. Biochem Biophys Res Commun 277: 643 649, 2000. Ohyama K, Ellis P, Kimura S, Placzek M. Directed differentiation of neural cells to hypothalamic dopaminergic neurons. Development 132: 51855197, 2005. Olson LE, Tollkuhn J, Scafoglio C, Krones A, Zhang J, Ohgi KA, Wu W, Taketo MM, Kemler R, Grosschedl R, Rose D, Li X, Rosenfeld MG. Homeodomain-mediated beta-catenin-dependent switching events dictate cell-lineage determination. Cell 125: 593 605, 2006. Ortiga-Carvalho TM, Shibusawa N, Nikrodhanond A, Oliveira KJ, Machado DS, Liao XH, Cohen RN, Refetoff S, Wondisford FE. Negative regulation by thyroid hormone receptor requires an intact coactivator-binding surface. J Clin Invest 115: 25172523, 2005. Ozaki H, Nakamura K, Funahashi J, Ikeda K, Yamada G, Tokano H, Okamura HO, Kitamura K, Muto S, Kotaki H, Sudo K, Horai R, Iwakura Y, Kawakami K. Six1 controls patterning of the mouse otic vesicle. Development 131: 551562, 2004. Ozaki H, Watanabe Y, Takahashi K, Kitamura K, Tanaka A, Urase K, Momoi T, Sudo K, Sakagami J, Asano M, Iwakura Y, Kawakami K. Six4, a putative myogenin gene regulator, is not essential for mouse embryonal development. Mol Cell Biol 21: 33433350, 2001. Palomino T, Barettino D, Aranda A. Role of GHF-1 in the regulation of the rat growth hormone gene promoter by thyroid hormone and retinoic acid receptors. J Biol Chem 273: 27541 27547, 1998. Palomino T, Sanchez-Pacheco A, Pena P, Aranda A. A direct protein-protein interaction is involved in the cooperation between thyroid hormone and retinoic acid receptors and the transcription factor GHF-1. FASEB J 12: 12011209, 1998. Park HL, Bai C, Platt KA, Matise MP, Beeghly A, Hui CC, Nakashima M, Joyner AL. Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation. Development 127: 15931605, 2000. Parker KL, Rice DA, Lala DS, Ikeda Y, Luo X, Wong M, Bakke M, Zhao L, Frigeri C, Hanley NA, Stallings N, Schimmer BP. Steroidogenic factor 1: an essential mediator of endocrine development. Recent Prog Horm Res 57: 19 36, 2002. Pask AJ, Kanasaki H, Kaiser UB, Conn PM, Janovick JA, Stockton DW, Hess DL, Justice MJ, Behringer RR. A novel mouse model of hypogonadotrophic hypogonadism: N-ethyl-Nnitrosourea-induced gonadotropin-releasing hormone receptor gene mutation. Mol Endocrinol 19: 972981, 2005. Philips A, Lesage S, Gingras R, Maira MH, Gauthier Y, Hugo P, Drouin J. Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells. Mol Cell Biol 17: 5946 5951, 1997. Philips A, Maira M, Mullick A, Chamberland M, Lesage S, Hugo P, Drouin J. Antagonism between Nur77 and glucocorticoid receptor for control of transcription. Mol Cell Biol 17: 59525959, 1997. Pogoda HM, von der Hardt S, Herzog W, Kramer C, Schwarz H, Hammerschmidt M. The proneural gene ascl1a is required for endocrine differentiation and cell survival in the zebrash adenohypophysis. Development 133: 1079 1089, 2006. Poulin G, Lebel M, Chamberland M, Paradis FW, Drouin J. Specic protein-protein interaction between basic helix-loop-helix transcription factors and homeoproteins of the Pitx family. Mol Cell Biol 20: 4826 4837, 2000. www.prv.org
183. MacColl G, Quinton R, Bouloux PM. GnRH neuronal development: insights into hypogonadotrophic hypogonadism. Trends Endocrinol Metab 13: 112118, 2002. 184. Maira M, Couture C, Le Martelot G, Pulichino AM, Bilodeau S, Drouin J. The T-box factor Tpit recruits SRC/p160 co-activators and mediates hormone action. J Biol Chem 278: 46523 46532, 2003. 185. Maira M, Martens C, Philips A, Drouin J. Heterodimerization between members of the Nur subfamily of orphan nuclear receptors as a novel mechanism for gene activation. Mol Cell Biol 19: 7549 7557, 1999. 186. Martens C, Bilodeau S, Maira M, Gauthier Y, Drouin J. Protein-protein interactions and transcriptional antagonism between the subfamily of NGFI-B/Nur77 orphan nuclear receptors and glucocorticoid receptor. Mol Endocrinol 19: 885 897, 2005. 187. Martinez-Barbera JP, Rodriguez TA, Beddington RS. The homeobox gene Hesx1 is required in the anterior neural ectoderm for normal forebrain formation. Dev Biol 223: 422 430, 2000. 188. Maruoka Y, Ohbayashi N, Hoshikawa M, Itoh N, Hogan BL, Furuta Y. Comparison of the expression of three highly related genes, Fgf8, Fgf17 and Fgf18, in the mouse embryo. Mech Dev 74: 175177, 1998. 189. Matzuk MM, Kumar TR, Bradley A. Different phenotypes for mice decient in either activins or activin receptor type II. Nature 374: 356 360, 1995. 190. Michaud JL, DeRossi C, May NR, Holdener BC, Fan CM. ARNT2 acts as the dimerization partner of SIM1 for the development of the hypothalamus. Mech Dev 90: 253261, 2000. 191. Michaud JL, Rosenquist T, May NR, Fan CM. Development of neuroendocrine lineages requires the bHLH-PAS transcription factor SIM1. Genes Dev 12: 3264 3275, 1998. 192. Miller WL, Shaee-Kermani F, Strahl BD, Huang HJ. The nature of FSH induction by GnRH. Trends Endocrinol Metab 13: 257263, 2002. 193. Mullis PE. Genetic control of growth. Eur J Endocrinol 152: 1131, 2005. 194. Muscatelli F, Abrous DN, Massacrier A, Boccaccio I, Le Moal M, Cau P, Cremer H. Disruption of the mouse Necdin gene results in hypothalamic and behavioral alterations reminiscent of the human Prader-Willi syndrome. Hum Mol Genet 9: 31013110, 2000. 195. Mutsuga N, Iwasaki Y, Morishita M, Nomura A, Yamamori E, Yoshida M, Asai M, Ozaki N, Kambe F, Seo H, Oiso Y, Saito H. Homeobox protein Gsh-1-dependent regulation of the rat GHRH gene promoter. Mol Endocrinol 15: 2149 2156, 2001. 196. Mynard V, Guignat L, Devin-Leclerc J, Bertagna X, Catelli MG. Different mechanisms for leukemia inhibitory factor-dependent activation of two proopiomelanocortin promoter regions. Endocrinology 143: 3916 3924, 2002. 197. Naiche LA, Harrelson Z, Kelly RG, Papaioannou VE. T-box genes in vertebrate development. Annu Rev Genet 39: 219 239, 2005. 198. Nakai S, Kawano H, Yudate T, Nishi M, Kuno J, Nagata A, Jishage K, Hamada H, Fujii H, Kawamura K, Shiba K, Noda T. The POU domain transcription factor Brn-2 is required for the determination of specic neuronal lineages in the hypothalamus of the mouse. Genes Dev 9: 3109 3121, 1995. 199. Nasonkin IO, Ward RD, Raetzman LT, Seasholtz AF, Saunders TL, Gillespie PJ, Camper SA. Pituitary hypoplasia and respiratory distress syndrome in Prop1 knockout mice. Hum Mol Genet 13: 27272735, 2004. 200. Naya FJ, Huang HP, Qiu Y, Mutoh H, DeMayo FJ, Leiter AB, Tsai MJ. Diabetes, defective pancreatic morphogenesis, abnormal enteroendocrine differentiation in BETA2/neuroD-decient mice. Genes Dev 11: 23232334, 1997. 201. Nica G, Herzog W, Sonntag C, Hammerschmidt M. Zebrash pit1 mutants lack three pituitary cell types and develop severe dwarsm. Mol Endocrinol 18: 1196 1209, 2004. 202. Nica G, Herzog W, Sonntag C, Nowak M, Schwarz H, Zapata AG, Hammerschmidt M. Eya1 is required for lineage-specic differentiation, but not for cell survival in the zebrash adenohypophysis. Dev Biol 292: 189 204, 2006. 203. Norlin S, Nordstrom U, Edlund T. Fibroblast growth factor signaling is required for the proliferation and patterning of progenPhysiol Rev VOL
204.
205.
206.
207.
208.
209.
210.
211.
212.
213.
214.
215.
216.
217.
218.
219.
220.
87 JULY 2007
MOLECULAR PHYSIOLOGY OF PITUITARY DEVELOPMENT 221. Poulin G, Turgeon B, Drouin J. NeuroD1/beta2 contributes to cell-specic transcription of the proopiomelanocortin gene. Mol Cell Biol 17: 6673 6682, 1997. 222. Pulichino AM, Vallette-Kasic S, Couture C, Gauthier Y, Brue T, David M, Malpuech G, Deal C, Van Vliet G, De Vroede M, Riepe FG, Partsch CJ, Sippell WG, Berberoglu M, Atasay B, Drouin J. Human and mouse TPIT gene mutations cause early onset pituitary ACTH deciency. Genes Dev 17: 711716, 2003. 223. Pulichino AM, Vallette-Kasic S, Tsai JP, Couture C, Gauthier Y, Drouin J. Tpit determines alternate fates during pituitary cell differentiation. Genes Dev 17: 738 747, 2003. 224. Quentien MH, Manfroid I, Moncet D, Gunz G, Muller M, Grino M, Enjalbert A, Pellegrini I. Pitx factors are involved in basal and hormone-regulated activity of the human prolactin promoter. J Biol Chem 277: 44408 44416, 2002. 225. Quirk CC, Lozada KL, Keri RA, Nilson JH. A single Pitx1 binding site is essential for activity of the LHbeta promoter in transgenic mice. Mol Endocrinol 15: 734 746, 2001. 226. Raetzman LT, Ross SA, Cook S, Dunwoodie SL, Camper SA, Thomas PQ. Developmental regulation of Notch signaling genes in the embryonic pituitary: Prop1 deciency affects Notch2 expression. Dev Biol 265: 329 340, 2004. 227. Raetzman LT, Ward R, Camper SA. Lhx4 and Prop1 are required for cell survival and expansion of the pituitary primordia. Development 129: 4229 4239, 2002. 228. Raetzman LT, Wheeler BS, Ross SA, Thomas PQ, Camper SA. Persistent expression of Notch2 delays gonadotrope differentiation. Mol Endocrinol 20: 2898 2908, 2006. 229. Rayapureddi JP, Kattamuri C, Steinmetz BD, Frankfort BJ, Ostrin EJ, Mardon G, Hegde RS. Eyes absent represents a class of protein tyrosine phosphatases. Nature 426: 295298, 2003. 230. Rebay I, Silver SJ, Tootle TL. New vision from Eyes absent: transcription factors as enzymes. Trends Genet 21: 163171, 2005. 231. Reichardt HM, Kaestner KH, Wessely O, Gass P, Schmid W, Schutz G. Analysis of glucocorticoid signalling by gene targeting. J Steroid Biochem Mol Biol 65: 111115, 1998. 232. Reichardt HM, Schutz G. Feedback control of glucocorticoid production is established during fetal development. Mol Med 2: 735744, 1996. 233. Revest JM, Spencer-Dene B, Kerr K, De Moerlooze L, Rosewell I, Dickson C. Fibroblast growth factor receptor 2-IIIb acts upstream of Shh and Fgf4 and is required for limb bud maintenance but not for the induction of Fgf8, Fgf10, Msx1, or Bmp4. Dev Biol 231: 47 62, 2001. 234. Revest JM, Suniara RK, Kerr K, Owen JJ, Dickson C. Development of the thymus requires signaling through the broblast growth factor receptor R2-IIIb. J Immunol 167: 1954 1961, 2001. 235. Rhodes SJ, Chen R, DiMattia GE, Scully KM, Kalla KA, Lin SC, Yu VC, Rosenfeld MG. A tissue-specic enhancer confers Pit-1-dependent morphogen inducibility and autoregulation on the pit-1 gene. Genes Dev 7: 913932, 1993. 236. Rizzoti K, Brunelli S, Carmignac D, Thomas PQ, Robinson IC, Lovell-Badge R. SOX3 is required during the formation of the hypothalamo-pituitary axis. Nat Genet 36: 247255, 2004. 237. Rizzoti K, Lovell-Badge R. Early development of the pituitary gland: induction and shaping of Rathkes pouch. Rev Endocr Metab Disord 6: 161172, 2005. 238. Roberson MS, Misra-Press A, Laurance ME, Stork PJ, Maurer RA. A role for mitogen-activated protein kinase in mediating activation of the glycoprotein hormone alpha-subunit promoter by gonadotropin-releasing hormone. Mol Cell Biol 15: 35313539, 1995. 239. Roberson MS, Schoderbek WE, Tremml G, Maurer RA. Activation of the glycoprotein hormone alpha-subunit promoter by a LIM-homeodomain transcription factor. Mol Cell Biol 14: 2985 2993, 1994. 240. Roh M, Paterson AJ, Asa SL, Chin E, Kudlow JE. Stage-sensitive blockade of pituitary somatomammotrope development by targeted expression of a dominant negative epidermal growth factor receptor in transgenic mice. Mol Endocrinol 15: 600 613, 2001. 241. Rosenberg SB, Mellon PL. An Otx-related homeodomain protein binds an LHbeta promoter element important for activation during gonadotrope maturation. Mol Endocrinol 16: 1280 1298, 2002. Physiol Rev VOL
961
242. Saiardi A, Bozzi Y, Baik JH, Borrelli E. Antiproliferative role of dopamine: loss of D2 receptors causes hormonal dysfunction and pituitary hyperplasia. Neuron 19: 115126, 1997. 243. Sarapura VD, Strouth HL, Wood WM, Gordon DF, Ridgway EC. Activation of the glycoprotein hormone alpha-subunit gene promoter in thyrotropes. Mol Cell Endocrinol 146: 77 86, 1998. 244. Sasaki S, Lesoon-Wood LA, Dey A, Kuwata T, Weintraub BD, Humphrey G, Yang WM, Seto E, Yen PM, Howard BH, Ozato K. Ligand-induced recruitment of a histone deacetylase in the negative-feedback regulation of the thyrotropin beta gene. EMBO J 18: 5389 5398, 1999. 245. Savage JJ, Yaden BC, Kiratipranon P, Rhodes SJ. Transcriptional control during mammalian anterior pituitary development. Gene 319: 119, 2003. 246. Sbrogna JL, Barresi MJ, Karlstrom RO. Multiple roles for Hedgehog signaling in zebrash pituitary development. Dev Biol 254: 19 35, 2003. 247. Schaufele F, West BL, Baxter JD. Synergistic activation of the rat growth hormone promoter by Pit-1 and the thyroid hormone receptor. Mol Endocrinol 6: 656 665, 1992. 248. Schonemann MD, Ryan AK, McEvilly RJ, OConnell SM, Arias CA, Kalla KA, Li P, Sawchenko PE, Rosenfeld MG. Development and survival of the endocrine hypothalamus and posterior pituitary gland requires the neuronal POU domain factor Brn-2. Genes Dev 9: 31223135, 1995. 249. Schuff KG, Hentges ST, Kelly MA, Binart N, Kelly PA, Iuvone PM, Asa SL, Low MJ. Lack of prolactin receptor signaling in mice results in lactotroph proliferation and prolactinomas by dopaminedependent and -independent mechanisms. J Clin Invest 110: 973 981, 2002. 250. Schwarting GA, Kostek C, Bless EP, Ahmad N, Tobet SA. Deleted in colorectal cancer (DCC) regulates the migration of luteinizing hormone-releasing hormone neurons to the basal forebrain. J Neurosci 21: 911919, 2001. 251. Schwarting GA, Raitcheva D, Bless EP, Ackerman SL, Tobet S. Netrin 1-mediated chemoattraction regulates the migratory pathway of LHRH neurons. Eur J Neurosci 19: 1120, 2004. 252. Schweppe RE, Melton AA, Brodsky KS, Aveline LD, Resing KA, Ahn NG, Gutierrez-Hartmann A. Purication and mass spectrometric identication of GA-binding protein (GABP) as the functional pituitary Ets factor binding to the basal transcription element of the prolactin promoter. J Biol Chem 278: 1686316872, 2003. 253. Scully KM, Gleiberman AS, Lindzey J, Lubahn DB, Korach KS, Rosenfeld MG. Role of estrogen receptor-alpha in the anterior pituitary gland. Mol Endocrinol 11: 674 681, 1997. 254. Scully KM, Jacobson EM, Jepsen K, Lunyak V, Viadiu H, Carriere C, Rose DW, Hooshmand F, Aggarwal AK, Rosenfeld MG. Allosteric effects of Pit-1 DNA sites on long-term repression in cell type specication. Science 290: 11271131, 2000. 255. Scully KM, Rosenfeld MG. Pituitary development: regulatory codes in mammalian organogenesis. Science 295: 22312235, 2002. 256. Semina EV, Reiter R, Leysens NJ, Alward WL, Small KW, Datson NA, Siegel-Bartelt J, Bierke-Nelson D, Bitoun P, Zabel BU, Carey JC, Murray JC. Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet 14: 392399, 1996. 257. Sheng HZ, Moriyama K, Yamashita T, Li H, Potter SS, Mahon KA, Westphal H. Multistep control of pituitary organogenesis. Science 278: 1809 1812, 1997. 258. Sheng HZ, Westphal H. Early steps in pituitary organogenesis. Trends Genet 15: 236 240, 1999. 259. Sheng HZ, Zhadanov AB, Mosinger B Jr, Fujii T, Bertuzzi S, Grinberg A, Lee EJ, Huang SP, Mahon KA, Westphal H. Specication of pituitary cell lineages by the LIM homeobox gene Lhx3. Science 272: 1004 1007, 1996. 260. Shewchuk BM, Asa SL, Cooke NE, Liebhaber SA. Pit-1 binding sites at the somatotrope-specic DNase I hypersensitive sites I, II of the human growth hormone locus control region are essential for in vivo hGH-N gene activation. J Biol Chem 274: 3572535733, 1999. 261. Shewchuk BM, Ho Y, Liebhaber SA, Cooke NE. A single base difference between Pit-1 binding sites at the hGH promoter and www.prv.org
87 JULY 2007
962
ZHU, GLEIBERMAN, AND ROSENFELD locus control region species distinct Pit-1 conformations and functions. Mol Cell Biol 26: 6535 6546, 2006. Shewchuk BM, Liebhaber SA, Cooke NE. Specication of unique Pit-1 activity in the hGH locus control region. Proc Natl Acad Sci USA 99: 11784 11789, 2002. Shibusawa N, Hollenberg AN, Wondisford FE. Thyroid hormone receptor DNA binding is required for both positive and negative gene regulation. J Biol Chem 278: 732738, 2003. Shima Y, Zubair M, Ishihara S, Shinohara Y, Oka S, Kimura S, Okamoto S, Minokoshi Y, Suita S, Morohashi K. Ventromedial hypothalamic nucleus-specic enhancer of Ad4BP/SF-1 gene. Mol Endocrinol 19: 28122823, 2005. Shinoda K, Lei H, Yoshii H, Nomura M, Nagano M, Shiba H, Sasaki H, Osawa Y, Ninomiya Y, Niwa O, Morohashi KI, Li E. Developmental defects of the ventromedial hypothalamic nucleus and pituitary gonadotroph in the Ftz-F1 disrupted mice. Dev Dyn 204: 2229, 1995. Showalter AD, Smith TP, Bennett GL, Sloop KW, Whitsett JA, Rhodes SJ. Differential conservation of transcriptional domains of mammalian Prophet of Pit-1 proteins revealed by structural studies of the bovine gene and comparative functional analysis of the protein. Gene 291: 211221, 2002. Silver SJ, Davies EL, Doyon L, Rebay I. Functional dissection of eyes absent reveals new modes of regulation within the retinal determination gene network. Mol Cell Biol 23: 5989 5999, 2003. Silver SJ, Rebay I. Signaling circuitries in development: insights from the retinal determination gene network. Development 132: 313, 2005. Simmons DM, Voss JW, Ingraham HA, Holloway JM, Broide RS, Rosenfeld MG, Swanson LW. Pituitary cell phenotypes involve cell-specic Pit-1 mRNA translation and synergistic interactions with other classes of transcription factors. Genes Dev 4: 695711, 1990. Simpson TI, Price DJ. Pax6: a pleiotropic player in development. Bioessays 24: 10411051, 2002. Sloop KW, Parker GE, Hanna KR, Wright HA, Rhodes SJ. LHX3 transcription factor mutations associated with combined pituitary hormone deciency impair the activation of pituitary target genes. Gene 265: 61 69, 2001. Solomon NM, Ross SA, Morgan T, Belsky JL, Hol FA, Karnes PS, Hopwood NJ, Myers SE, Tan AS, Warne GL, Forrest SM, Thomas PQ. Array comparative genomic hybridisation analysis of boys with X linked hypopituitarism identies a 3.9 Mb duplicated critical region at Xq27 containing SOX3. J Med Genet 41: 669 678, 2004. Sornson MW, Wu W, Dasen JS, Flynn SE, Norman DJ, OConnell SM, Gukovsky I, Carriere C, Ryan AK, Miller AP, Zuo L, Gleiberman AS, Andersen B, Beamer WG, Rosenfeld MG. Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarsm. Nature 384: 327333, 1996. Suh H, Gage PJ, Drouin J, Camper SA. Pitx2 is required at multiple stages of pituitary organogenesis: pituitary primordium formation and cell specication. Development 129: 329 337, 2002. Suszko MI, Balkin DM, Chen Y, Woodruff TK. Smad3 mediates activin-induced transcription of follicle-stimulating hormone betasubunit gene. Mol Endocrinol 19: 1849 1858, 2005. Suszko MI, Lo DJ, Suh H, Camper SA, Woodruff TK. Regulation of the rat follicle-stimulating hormone beta-subunit promoter by activin. Mol Endocrinol 17: 318 332, 2003. Szeto DP, Rodriguez-Esteban C, Ryan AK, OConnell SM, Liu F, Kioussi C, Gleiberman AS, Izpisua-Belmonte JC, Rosenfeld MG. Role of the Bicoid-related homeodomain factor Pitx1 in specifying hindlimb morphogenesis and pituitary development. Genes Dev 13: 484 494, 1999. Szeto DP, Ryan AK, OConnell SM, Rosenfeld MG. P-OTX: a PIT-1-interacting homeodomain factor expressed during anterior pituitary gland development. Proc Natl Acad Sci USA 93: 7706 7710, 1996. Takuma N, Sheng HZ, Furuta Y, Ward JM, Sharma K, Hogan BL, Pfaff SL, Westphal H, Kimura S, Mahon KA. Formation of Rathkes pouch requires dual induction from the diencephalon. Development 125: 4835 4840, 1998. Physiol Rev VOL 280. Thomas P, Beddington R. Anterior primitive endoderm may be responsible for patterning the anterior neural plate in the mouse embryo. Curr Biol 6: 14871496, 1996. 281. Tobet S, Schwarting G. Minireview: recent progress in GnRH neuronal migration. Endocrinology 147: 1159 1165, 2005. 282. Tomita K, Moriyoshi K, Nakanishi S, Guillemot F, Kageyama R. Mammalian achaete-scute and atonal homologs regulate neuronal versus glial fate determination in the central nervous system. EMBO J 19: 5460 5472, 2000. 283. Tootle TL, Silver SJ, Davies EL, Newman V, Latek RR, Mills IA, Selengut JD, Parlikar BE, Rebay I. The transcription factor Eyes absent is a protein tyrosine phosphatase. Nature 426: 299 302, 2003. 284. Topilko P, Levi G, Merlo G, Mantero S, Desmarquet C, Mancardi G, Charnay P. Differential regulation of the zinc nger genes Krox-20 and Krox-24 (Egr-1) suggests antagonistic roles in Schwann cells. J Neurosci Res 50: 702712, 1997. 285. Treier M, Gleiberman AS, OConnell SM, Szeto DP, McMahon JA, McMahon AP, Rosenfeld MG. Multistep signaling requirements for pituitary organogenesis in vivo. Genes Dev 12: 16911704, 1998. 286. Treier M, OConnell S, Gleiberman A, Price J, Szeto DP, Burgess R, Chuang PT, McMahon AP, Rosenfeld MG. Hedgehog signaling is required for pituitary gland development. Development 128: 377386, 2001. 287. Treier M, Rosenfeld MG. The hypothalamic-pituitary axis: codevelopment of two organs. Curr Opin Cell Biol 8: 833 843, 1996. 288. Tremblay JJ, Drouin J. Egr-1 is a downstream effector of GnRH and synergizes by direct interaction with Ptx1 and SF-1 to enhance luteinizing hormone beta gene transcription. Mol Cell Biol 19: 2567 2576, 1999. 289. Tremblay JJ, Goodyer CG, Drouin J. Transcriptional properties of Ptx1 and Ptx2 isoforms. Neuroendocrinology 71: 277286, 2000. 290. Tremblay JJ, Lanctot C, Drouin J. The pan-pituitary activator of transcription, Ptx1 (pituitary homeobox 1), acts in synergy with SF-1 and Pit1 and is an upstream regulator of the Lim-homeodomain gene Lim3/Lhx3. Mol Endocrinol 12: 428 441, 1998. 291. Tremblay Y, Tretjakoff I, Peterson A, Antakly T, Zhang CX, Drouin J. Pituitary-specic expression and glucocorticoid regulation of a proopiomelanocortin fusion gene in transgenic mice. Proc Natl Acad Sci USA 85: 8890 8894, 1988. 292. Tsai PS, Moenter SM, Postigo HR, El Majdoubi M, Pak TR, Gill JC, Paruthiyil S, Werner S, Weiner RI. Targeted expression of a dominant-negative broblast growth factor (FGF) receptor in gonadotropin-releasing hormone (GnRH) neurons reduces FGF responsiveness and the size of GnRH neuronal population. Mol Endocrinol 19: 225236, 2005. 293. Vallette-Kasic S, Brue T, Pulichino AM, Gueydan M, Barlier A, David M, Nicolino M, Malpuech G, Dechelotte P, Deal C, Van Vliet G, De Vroede M, Riepe FG, Partsch CJ, Sippell WG, Berberoglu M, Atasay B, de Zegher F, Beckers D, Kyllo J, Donohoue P, Fassnacht M, Hahner S, Allolio B, Noordam C, Dunkel L, Hero M, Pigeon B, Weill J, Yigit S, Brauner R, Heinrich JJ, Cummings E, Riddell C, Enjalbert A, Drouin J. Congenital isolated adrenocorticotropin deciency: an underestimated cause of neonatal death, explained by TPIT gene mutations. J Clin Endocrinol Metab 90: 13231331, 2005. 294. Vasilyev VV, Pernasetti F, Rosenberg SB, Barsoum MJ, Austin DA, Webster NJ, Mellon PL. Transcriptional activation of the ovine follicle-stimulating hormone-beta gene by gonadotropin-releasing hormone involves multiple signal transduction pathways. Endocrinology 143: 16511659, 2002. 295. Vesper AH, Raetzman LT, Camper SA. Role of prophet of Pit1 (PROP1) in gonadotrope differentiation and puberty. Endocrinology 147: 1654 1663, 2006. 296. Wang W, Grimmer JF, Van De Water TR, Lufkin T. Hmx2 and Hmx3 homeobox genes direct development of the murine inner ear and hypothalamus and can be functionally replaced by Drosophila Hmx. Dev Cell 7: 439 453, 2004. 297. Wang W, Lufkin T. The murine Otp homeobox gene plays an essential role in the specication of neuronal cell lineages in the developing hypothalamus. Dev Biol 227: 432 449, 2000. www.prv.org
262.
263.
264.
265.
266.
267.
268.
269.
270. 271.
272.
273.
274.
275.
276.
277.
278.
279.
87 JULY 2007
MOLECULAR PHYSIOLOGY OF PITUITARY DEVELOPMENT 298. Wang W, Zhang C, Marimuthu A, Krupka HI, Tabrizizad M, Shelloe R, Mehra U, Eng K, Nguyen H, Settachatgul C, Powell B, Milburn MV, West BL. The crystal structures of human steroidogenic factor-1 and liver receptor homologue-1. Proc Natl Acad Sci USA 102: 75057510, 2005. 299. Ward RD, Raetzman LT, Suh H, Stone BM, Nasonkin IO, Camper SA. Role of PROP1 in pituitary gland growth. Mol Endocrinol 19: 698 710, 2005. 300. Ware CB, Kariagina A, Zonis S, Alon D, Chesnokova V. Leukemia inhibitory factor signaling is implicated in embrionic development of the HPA axis. FEBS Lett 579: 4465 4469, 2005. 301. Watanabe YG. Effects of brain and mesenchyme upon the cytogenesis of rat adenohypophysis in vitro. II. Differentiation of LH cells. Cell Tissue Res 242: 49 55, 1985. 302. Watkins-Chow DE, Camper SA. How many homeobox genes does it take to make a pituitary gland? Trends Genet 14: 284 290, 1998. 303. Watters JJ, Chun TY, Kim YN, Bertics PJ, Gorski J. Estrogen modulation of prolactin gene expression requires an intact mitogen-activated protein kinase signal transduction pathway in cultured rat pituitary cells. Mol Endocrinol 14: 18721881, 2000. 304. Wawersik S, Maas RL. Vertebrate eye development as modeled in Drosophila. Hum Mol Genet 9: 917925, 2000. 305. West BE, Parker GE, Savage JJ, Kiratipranon P, Toomey KS, Beach LR, Colvin SC, Sloop KW, Rhodes SJ. Regulation of the follicle-stimulating hormone beta gene by the LHX3 LIM-homeodomain transcription factor. Endocrinology 145: 4866 4879, 2004. 306. Whitlock KE. Origin and development of GnRH neurons. Trends Endocrinol Metab 16: 145151, 2005. 307. Wierman ME, Pawlowski JE, Allen MP, Xu M, Linseman DA, Nielsen-Preiss S. Molecular mechanisms of gonadotropin-releasing hormone neuronal migration. Trends Endocrinol Metab 15: 96 102, 2004. 308. Wilson SW, Houart C. Early steps in the development of the forebrain. Dev Cell 6: 167181, 2004. 309. Wolfe MW. The equine luteinizing hormone beta-subunit promoter contains two functional steroidogenic factor-1 response elements. Mol Endocrinol 13: 14971510, 1999. 310. Wolfe MW, Call GB. Early growth response protein 1 binds to the luteinizing hormone-beta promoter and mediates gonadotropinreleasing hormone-stimulated gene expression. Mol Endocrinol 13: 752763, 1999. 311. Wood WM, Dowding JM, Gordon DF, Ridgway EC. An upstream regulator of the glycoprotein hormone alpha-subunit gene mediates pituitary cell type activation and repression by different mechanisms. J Biol Chem 274: 15526 15532, 1999. 312. Wood WM, Dowding JM, Sarapura VD, McDermott MT, Gordon DF, Ridgway EC. Functional interactions of an upstream enhancer of the mouse glycoprotein hormone alpha-subunit gene with proximal promoter sequences. Mol Cell Endocrinol 142: 141 152, 1998. 313. Wood WM, Kao MY, Gordon DF, Ridgway EC. Thyroid hormone regulates the mouse thyrotropin beta-subunit gene promoter in transfected primary thyrotropes. J Biol Chem 264: 14840 14847, 1989. 314. Wray S. Molecular mechanisms for migration of placodally derived GnRH neurons. Chem Senses 27: 569 572, 2002. 315. Wu W, Cogan JD, Pfafe RW, Dasen JS, Frisch H, OConnell SM, Flynn SE, Brown MR, Mullis PE, Parks JS, Phillips JA
963
316.
317.
318.
319.
320.
321.
322.
323.
324.
325. 326.
327.
328.
329.
330.
331.
3rd, Rosenfeld MG. Mutations in PROP1 cause familial combined pituitary hormone deciency. Nat Genet 18: 147149, 1998. Xu J, Liu Z, Ornitz DM. Temporal and spatial gradients of Fgf8 and Fgf17 regulate proliferation and differentiation of midline cerebellar structures. Development 127: 18331843, 2000. Xu L, Lavinsky RM, Dasen JS, Flynn SE, McInerney EM, Mullen TM, Heinzel T, Szeto D, Korzus E, Kurokawa R, Aggarwal AK, Rose DW, Glass CK, Rosenfeld MG. Signalspecic co-activator domain requirements for Pit-1 activation. Nature 395: 301306, 1998. Xu PX, Adams J, Peters H, Brown MC, Heaney S, Maas R. Eya1-decient mice lack ears and kidneys and show abnormal apoptosis of organ primordia. Nat Genet 23: 113117, 1999. Xu PX, Cheng J, Epstein JA, Maas RL. Mouse Eya genes are expressed during limb tendon development and encode a transcriptional activation function. Proc Natl Acad Sci USA 94: 11974 11979, 1997. Xu PX, Zheng W, Huang L, Maire P, Laclef C, Silvius D. Six1 is required for the early organogenesis of mammalian kidney. Development 130: 30853094, 2003. Yano H, Readhead C, Nakashima M, Ren SG, Melmed S. Pituitary-directed leukemia inhibitory factor transgene causes Cushings syndrome: neuro-immune-endocrine modulation of pituitary development. Mol Endocrinol 12: 1708 1720, 1998. Zakaria MM, Jeong KH, Lacza C, Kaiser UB. Pituitary homeobox 1 activates the rat FSHbeta (rFSHbeta) gene through both direct and indirect interactions with the rFSHbeta gene promoter. Mol Endocrinol 16: 1840 1852, 2002. Zanger K, Radovick S, Wondisford FE. CREB binding protein recruitment to the transcription complex requires growth factordependent phosphorylation of its GF box. Mol Cell 7: 551558, 2001. Zhao L, Bakke M, Hanley NA, Majdic G, Stallings NR, Jeyasuria P, Parker KL. Tissue-specic knockouts of steroidogenic factor 1. Mol Cell Endocrinol 215: 89 94, 2004. Zhao L, Bakke M, Parker KL. Pituitary-specic knockout of steroidogenic factor 1. Mol Cell Endocrinol 185: 2732, 2001. Zhao Y, Morales DC, Hermesz E, Lee WK, Pfaff SL, Westphal H. Reduced expression of the LIM-homeobox gene Lhx3 impairs growth and differentiation of Rathkes pouch and increases cell apoptosis during mouse pituitary development. Mech Dev 123: 605 613, 2006. Zheng W, Huang L, Wei ZB, Silvius D, Tang B, Xu PX. The role of Six1 in mammalian auditory system development. Development 130: 3989 4000, 2003. Zhu X, Lin CR, Prefontaine GG, Tollkuhn J, Rosenfeld MG. Genetic control of pituitary development and hypopituitarism. Curr Opin Genet Dev 15: 332340, 2005. Zhu X, Rosenfeld MG. Transcriptional control of precursor proliferation in the early phases of pituitary development. Curr Opin Genet Dev 14: 567574, 2004. Zhu X, Zhang J, Tollkuhn J, Ohsawa R, Bresnick EH, Guillemot F, Kageyama R, Rosenfeld MG. Sustained Notch signaling in progenitors is required for sequential emergence of distinct cell lineages during organogenesis. Genes Dev 20: 2739 2753, 2006. Zou D, Silvius D, Fritzsch B, Xu PX. Eya1 and Six1 are essential for early steps of sensory neurogenesis in mammalian cranial placodes. Development 131: 55615572, 2004.
Physiol Rev VOL
87 JULY 2007
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Molecular Physiology of Pituitary Development: Signaling and Transcriptional Networks

Xiaoyan Zhu, Anatoli S. Gleiberman and Michael G. Rosenfeld
Physiol Rev 87:933-963, 2007. doi:10.1152/physrev.00006.2006 You might find this additional info useful... This article cites 331 articles, 191 of which can be accessed free at: http://physrev.physiology.org/content/87/3/933.full.html#ref-list-1 This article has been cited by 25 other HighWire hosted articles, the first 5 are: Pulsatile patterns of pituitary hormone gene expression change during development Karen Featherstone, Claire V. Harper, Anne McNamara, Sabrina Semprini, David G. Spiller, Judith McNeilly, Alan S. McNeilly, John J. Mullins, Michael R. H. White and Julian R. E. Davis J Cell Sci, October 15, 2011; 124 (20): 3484-3491. [Abstract] [Full Text] [PDF] Novel FGF8 Mutations Associated with Recessive Holoprosencephaly, Craniofacial Defects, and Hypothalamo-Pituitary Dysfunction Mark J. McCabe, Carles Gaston-Massuet, Vaitsa Tziaferi, Louise C. Gregory, Kyriaki S. Alatzoglou, Massimo Signore, Eduardo Puelles, Dianne Gerrelli, I. Sadaf Farooqi, Jamal Raza, Joanna Walker, Scott I. Kavanaugh, Pei-San Tsai, Nelly Pitteloud, Juan-Pedro Martinez-Barbera and Mehul T. Dattani JCEM, October , 2011; 96 (10): E1709-E1718. [Abstract] [Full Text] [PDF] Related pituitary cell lineages develop into interdigitated 3D cell networks Lionel Budry, Chrystel Lafont, Taoufik El Yandouzi, Norbert Chauvet, Genevive Conjero, Jacques Drouin and Patrice Mollard PNAS, July 26, 2011; 108 (30): 12515-12520. [Abstract] [Full Text] [PDF] FGF-dependent midline-derived progenitor cells in hypothalamic infundibular development Caroline Alayne Pearson, Kyoji Ohyama, Liz Manning, Soheil Aghamohammadzadeh, Helen Sang and Marysia Placzek Development, June 15, 2011; 138 (12): 2613-2624. [Abstract] [Full Text] [PDF] The Role of the hGH Locus Control Region in Somatotrope Restriction of hGH-N Gene Expression Yugong Ho, Stephen A. Liebhaber and Nancy E. Cooke Molecular Endocrinology, May , 2011; 25 (5): 877-884. [Abstract] [Full Text] [PDF] Updated information and services including high resolution figures, can be found at: http://physrev.physiology.org/content/87/3/933.full.html Additional material and information about Physiological Reviews can be found at: http://www.the-aps.org/publications/prv
Physiological Reviews provides state of the art coverage of timely issues in the physiological and biomedical sciences. It is published quarterly in January, April, July, and October by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright 2007 by the American Physiological Society. ISSN: 0031-9333, ESSN: 1522-1210. Visit our website at http://www.the-aps.org/.
This infomation is current as of October 28, 2011.
Physiological Reviews provides state of the art coverage of timely issues in the physiological and biomedical sciences. It is published quarterly in January, April, July, and October by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright 2007 by the American Physiological Society. ISSN: 0031-9333, ESSN: 1522-1210. Visit our website at http://www.the-aps.org/.

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Physiol Rev 87: 933963, 2007; doi:10.1152/physrev.00006.2006.

Molecular Physiology of Pituitary Development: Signaling and Transcriptional Networks

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