Ephrins

diger Klein, European Molecular Biology Laboratory, Heidelberg, Germany Ru

Ephrins are cell surface-associated or transmembrane proteins which can bind via their extracellular domain members of the Eph receptor tyrosine kinases. Ephrin Eph interactions can trigger a variety of responses, including axon and cellular guidance and patterning of brain structures.

Secondary article
Article Contents
. Introduction . Ephs and Ephrins . Gradients in Retinotectal Guidance . Role in Other Central Nervous Systems . Eph Receptor Signalling . Summary

Introduction
Navigating axons are guided to their targets by a multitude of extracellular signals that need to be recognized and transduced to intracellular messengers by receptors on the axonal growth cone (Tessier-Lavigne and Goodman, 1996). Ephrins, the ligands of Eph receptor tyrosine kinases, are cell surface proteins that belong to the class of repulsive axon guidance cues (Harris and Holt, 1995). Eph receptor signalling is required for correct formation of axon bundles in vivo. The subgroup of transmembrane ephrins can be expressed on navigating axons and may transduce a signal into the neuron when activated by the corresponding Eph receptor. Ephrins are likely to have additional functions in axon fasciculation, cell migration and patterning of embryonic structures.

ephrin-B ligands. Within each subgroup, receptors bind to more than one ligand, and ligands can activate more than one receptor. With the exception of the EphA4 receptor, which apparently binds both groups of ephrin ligands, little crosstalk has been observed between receptors and ligands of two dierent subgroups. Membrane attachment and clustering appears to be required for ephrins to activate receptors, because only membrane-bound or articially clustered ligands, but not soluble ligands, can trigger receptor signalling. Because Eph receptors and ephrins are
Ephrin-A Ephrin-B Cyto GPI Ext

Ephs and Ephrins

In vertebrates, the family of Eph receptor tyrosine kinases is comprised of at least 14 dierent members, each encoded by a dierent gene. The extracellular parts of Eph receptors contain a number of distinct domains (Figure 1), also found in other transmembrane proteins, including two bronectin-type III repeats, a cysteine-rich region with homology to epidermal growth factor (EGF)-like repeats and a structurally undened N-terminal globular domain, which constitutes the primary ligand-binding region. Based on the homology of their extracellular domains, Eph receptors are classied into two groups, eight EphA receptors (EphA1 to EphA8) and six EphB receptors (EphB1 to EphB6). The ligands of Eph receptors, known as ephrins (Eph receptor interacting proteins), comprise a family of eight cell surface proteins. They also fall into two groups (A and B) based on their mode of membrane attachment. Ephrin-A ligands (ephrin-A1 to ephrin-A5) are tethered to the cell surface via a glycosylphosphatidylinositol (GPI) anchor, whereas ephrin-B ligands (ephrin-B1 to ephrin-B3) contain a transmembrane domain and a cytoplasmic tail (Eph Nomenclature Committee, 1997). The separation of Eph receptors and ephrins into subgroups also reects their binding preferences: EphA receptors bind ephrin-A ligands, EphB receptors bind

Ext

Glob

Cys

Eph receptor

FN III FN III

TK

Figure 1 Receptors and ligands. Ephrin-A ligands are attached to the cell surface by a GPI-anchor, while ephrin-B ligands span the membrane and contain a cytoplasmic domain. Both subgroups of Eph receptors have the same overall structure. Domains: Cys, cysteine-rich; Cyto, cytoplasmic; Ext, extracellular; FNIII, fibronectin type III; Glob, globular; GPI, glycosylphosphatidylinositol anchor; TK, tyrosine kinase.

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both membrane-bound molecules, it is believed that they mediate direct cellcell communication rather than longrange interactions.

Gradients in Retinotectal Guidance

Many Eph receptors and ligands are specically expressed in the nervous system, where they present spatially restricted and dynamic expression patterns during embryonic development. In certain brain areas, Ephs and ephrins are expressed in complementary gradients in projecting neurons and their target elds, implicating them in the establishment of topographic projections. In this type of projection, axons of neighbouring neurons innervate neighbouring areas in the target eld. For example, in the chicken visual (retinotectal) system, axons of the anterior (nasal) retinal neurons project to the posterior area of the tectum, their target eld in the midbrain, and axons of the posterior (temporal) retinal neurons project to the anterior tectum (Figure 2). In the
Retina Tectum

(a)

EphA3

Ephrin-A2

EphA4 EphA5

Ephrin-A5

EphB2 (b)
Figure 2 Complementary gradients of Eph receptors and their ligands in the developing chick retinotectal system. (a) Axons from anterior (nasal, N) retinal ganglion cells project to posterior (P) tectum, whereas axons from the posterior (temporal, T) retina terminate in the anterior (A) tectum. (b) In the tectum (blue gradients), ephrin-A2 and -A5 show graded expression along the anteroposterior axis, with ephrin-A5 mostly confined to the posterior half. In the retina (red gradients), EphA3 receptors are expressed in an ascending A-P gradient, EphA5 is expressed uniformly, and EphB2 is expressed in an ascending dorsoventral gradient. The importance of the latter gradient is not well understood because ephrin-B ligands do not appear to be expressed in a complementary dorsoventral gradient in the tectum. (From Orioli D and Klein R (1997) Trends in Genetics 13: 354 359.)

same way, dorsal retinal axons project to the ventral tectum and ventral retinal axons project to the dorsal tectum. These neuronal topographic connections have the ability to transfer information from the projecting neurons (retina) to the target neurons (tectum) maintaining the original spatial order, and it allows the tectum to receive the same, but inverted, image that is captured by the retina. The use of in vitro axon guidance assays has been essential for providing evidence for possible functions of Eph proteins. In the stripe assay (Drescher et al., 1995), axons from retinal ganglion cells are allowed to extend and to choose among stripes of anterior and posterior tectal membranes, or alternatively among stripes of cells expressing and lacking dierent recombinant guidance molecules. This approach led to the identication of a repellent axon guidance activity for temporal retinal axons, now known as the GPI-anchored ligand ephrin-A5. This protein was shown to be expressed in the chicken tectum, in a decreasing posterior to anterior gradient (Figure 2), at the time when retinal axons reach the tectum and throughout the period axons make their nal contacts. Another ephrin ligand, ephrin-A2, is coexpressed in a similar gradient in the chicken tectum and appears to cooperate with ephrin-A5 to guide retinal ganglion axons. When retrovirally misexpressed in the tectum, ephrin-A2 causes temporal retinal ganglion cells to project to abnormal locations (Nakamoto et al., 1996). While the gradient of ephrin-A5 is very steep and mostly conned to the posterior region of the tectum, the ephrin-A2 gradient is much more linear (Figure 2). Therefore, retinal axons that enter the tectum are confronted with ephrin-A2-expressing cells before they encounter the ephrin-A5-expression domain. Interestingly, in the mouse, ephrin-A5 expression resembles that in the chicken, whereas ephrin-A2 expression is dierent. Levels of ephrin-A2 messenger ribonucleic acid (mRNA) (and protein) are high through much of the superior colliculus (SC), the target area of retinal ganglion cell axons, but low or nondetectable in caudal-most and rostral SC and inferior colliculus (IC), a nonretinal target. Functional data have recently been provided from the analysis of ephrin-A5-decient mice and suggest a dual function for this molecule (Frisen et al., 1998). First, in ephrin-A5 2 / 2 mice, temporal axons aberrantly arborize in parts of the SC where ephrin-A5 would normally be expressed (the caudal-most SC) and ephrin-A2 is expressed at low levels (caudal-most and rostral SC). It was proposed that ephrin-A2 and ephrin-A5 together form a smooth repellent gradient across the SC and cooperate to establish the normal topographic map. Second, in ephrin-A5decient mice, a substantial number of retinal axons overshoot the SC and extend aberrantly into the IC. Ephrin-A5 therefore acts as a barrier that inhibits the growth of retinal axons beyond the caudal limit of the SC. Among the receptors that are expressed on retinal ganglion cells, EphA3 appears to be the best candidate for mediating ephrin-A2/A5 repellent axon guidance activity,

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because EphA3 is expressed in a complementary anterior (nasal) to posterior (temporal) gradient (Figure 2) and, in vitro, it binds ephrin-A2/A5 with highest anity (Cheng et al., 1995; Monschau et al., 1997). Other Eph receptors, such as EphA4 and EphA5, are uniformly expressed in the retina. However, in absence of genetic or other functional in vivo experiments, the specic role of these EphA receptors in establishing topographic projections is not clear. Likewise, the establishment of the second, dorsoventral, axis is much less understood. Stripe assays have so far failed to yield any evidence of dorsoventral guidance activity in the retinotectal system, but there are proteins, like the EphB2 receptor, that clearly show a dorsoventral gradient of expression in retinal ganglion cells (Figure 2).

Role in Other Central Nervous Systems

The receptor EphA5 might be involved in another topographic map, the murine hippocamposeptal projection. In this case, EphA5 expression occurs in a lateral to medial gradient within the hippocampus, matched by a countergradient of several ephrin-A ligands in the septum, the target region of these neurons (Zhang et al., 1996). This expression pattern suggests that ephrin-A ligands might inhibit EphA5-expressing medial hippocampal neurons, and allow lateral hippocampal neurons to project to the ventrolateral septum. Consistent with this hypothesis, NIH3T3 cells expressing ephrin-A2 can inhibit neurite outgrowth from medial hippocampal but not lateral hippocampal neurons. Whether Ephs and ephrins are required for the establishment of the hippocamposeptal projection in vivo remains to be determined. Mutant mice decient for members of the Eph receptor family clearly reveal an essential role for these proteins in brain development. Mice decient for the receptor EphB2 show an aberrant formation of one of the midline-crossing bre tracts, so-called commissures, that connect the two brain hemispheres (Henkemeyer et al., 1996). The bres that normally interconnect the temporal cortex of the two hemispheres, the posterior part of the anterior commissure, in mutant mice, instead of crossing the midline, are misdirected to the ventral forebrain. This defect was shown not to be cell autonomous, because EphB2 was not expressed at signicant levels in the misdirected bres, but rather in the cells ventral to the pathway of migrating anterior commissure axons. This expression suggested that EphB2 has repulsive eects on commissural axons, thereby forcing them across the midline. However, an in vitro guidance assay will have to be developed using membranes from mutant mice to conrm this hypothesis. Mice decient for the receptor EphB3 show, albeit with incomplete penetrance, a defect in the corpus callosum, another commissural bre tract that interconnects the neocortex of the two hemispheres (Orioli et al., 1996). In

this case, the commissural bres, instead of crossing the midline, tend to accumulate near the midline on the ipsilateral side, or to change their orientation and run along the anteroposterior axis. Ligands of EphB2 and EphB3 are expressed by cultured cortical neurons, indicating that EphB2 and EphB3 are primarily involved in neuron-to-neuron signalling in the central nervous system. Given the large number of potential ligand receptor interactions within this family, molecules of the same subclass might have redundant functions, revealed only by the analysis of double mutant mice. In fact, mice that are decient for both receptors EphB2 and EphB3 show more severe axon guidance defects in the forebrain than the single mutants, and additional guidance defects in commissural projections of the dorsal midbrain, the habenular commissure. They also reveal axon bundling (fasciculation) defects, but not misrouting, in the habenular-interpeduncle tract, a bre tract that runs along the anteroposterior axis (Orioli et al., 1996). This suggests that Eph receptors can mediate repulsive signals from surrounding cells that push axons together. Interestingly, recent reports provide evidence for a signalling function of ephrin-B ligands. Genetic studies in the mouse indicate that anterior commissure axons are properly guided to the contralateral cortex by EphB2 receptors lacking a tyrosine kinase domain (at least in certain genetic backgrounds) (Henkemeyer et al., 1996). Thus, the interaction of the EphB2 extracellular domain expressed on surrounding cells with the corresponding ephrin-B ligands on anterior commissure axons is apparently sucient for proper guidance. Although there are several possible explanations for this phenomenon, a plausible and attractive interpretation would be that ephrin-B ligands expressed on anterior commissure axons can signal upon receptor EphB2 contact and that this signal is sucient to guide these axons across the midline. In a wild-type situation, this would at the same time elicit a signal in the EphB2-expressing cells via the activated receptor (Figure 3). Support for this hypothesis came from biochemical studies involving cell lines stably expressing ephrin-B ligands. The cytoplasmic domain of ephrin-B ligands becomes phosphorylated on tyrosine residues after contact with the corresponding receptors, EphB1 and EphB2, when presented by neighbouring cells (Holland et al., 1996). Moreover, ephrin-B ligands are found phosphorylated on tyrosine residues in the developing mouse embryo during periods of active axonal pathnding, indicating that this phosphorylation is physiologically relevant. Similar tyrosine phosphorylation of ephrin-B cytoplasmic domains is observed after stimulating the cells with growth factors, such as platelet-derived growth factor (PDGF), that signal through receptor tyrosine kinases, suggesting crosstalk between ephrin-B1 and signal cascades activated by growth factor receptors (Bru ckner et al., 1997). Focus formation assays in NIH3T3 broblasts have shown that the cytoplasmic domain of ephrin-B ligands
3

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Ephrins

Anterior commissure P P Cell body Signal P Axonal growth

P (a)

Spinal motor neurons P P P

Cell body

Signal

Axonal growth

P (b) ephrin-B ligand

EphB receptor
Figure 3 Model of bidirectional signalling by Eph receptors and ephrin-B ligands during axonal pathfinding. (a) Anterior commissure axons (and presumably their migrating growth cones) express ephrin-B ligands, whereas surrounding neurons express EphB receptors. Axons might be guided by contact repulsion involving bidirectional signalling downstream of ligands and receptors (arrows). Tyrosine phosphorylation (P) of both receptors and ligands are likely to contribute to or activate downstream signalling cascades. (b) Spinal motor neurons express EphB (and possibly EphA, not shown) receptors and appear to be guided by ephrin-B ligands in the caudal somites. Here, receptors transduce signals into the axon and ligands might signal into somitic cells. (From Orioli D and Klein R (1997) Trends in Genetics 13: 354 359.)

can inhibit the transforming activity of activated tyrosine kinases, suggesting that ephrin-B ligands have intrinsic signalling potential. Currently, several laboratories are involved in characterizing the signalling potential of proteins that specically interact with the cytoplasmic domain of ephrin-B ligands. The receptor EphA8 appears to control the formation of a bre tract that connects the SC of the midbrain with the contralateral IC. In ephA8-decient mice, a subpopulation of collicular neurons fails to reach targets within the contralateral IC and instead projects along an aberrant ipsilateral path that targets the cervical spinal cord (Park et al., 1997). Retrograde labelling of these aberrantly projecting neurons revealed that they express the EphA8 receptor, indicating a cell autonomous function in axonal pathnding of these collicular neurons. It is not known which of the several possible GPI-anchored ephrin-A

ligands represents the physiological repellent signal for these neurons. Complementary expression patterns have also been observed by in situ hybridization in the developing hindbrain, which, during early embryogenesis, is divided into segments called rhombomeres. For example, whereas the receptors EphA4, EphB2 and EphB3 are expressed in rhombomeres 3 and 5, some of the corresponding ligands, such as ephrin-B2 and ephrin-B3, are expressed in evennumbered rhombomeres (Friedman and OLeary, 1996). At the same time, cells in rhombomere 4 express the receptor EphA2. The rhombomere-restricted expression patterns suggest a role for these molecules in hindbrain segmentation. Indeed, injection of Xenopus and zebra sh embryos with a dominant-negative form of the receptor EphA4 disrupts the segmentally restricted expression of several markers in the hindbrain, suggesting a potential role for EphA4 in regulating the segmental cell identity and/or cell migration (Xu et al., 1995). The same approach also yielded evidence for a role of EphA4 in forebrain patterning. Inhibition of Rtk1, the zebra sh homologue of EphA4, resulted in the expansion of the eyeeld into diencephalic territory and loss of diencephalic structures (Xu et al., 1996). It is possible that Rtk1 signalling is required in diencephalic cells to maintain their identity, or that Rtk1 restricts cell movement, thereby preventing a switch from diencephalic identity to a retinal identity. In the peripheral nervous system, sensory and sympathetic neurons arise from a specic, highly migratory cell population, the neural crest cells. Rows of paravertebral sensory and sympathetic ganglia develop because neural crest migration is guided by inhibitory cues present in the caudal half of the somites. Motor axons projecting from the ventral neural tube also follow similar contactmediated guidance cues. Recent work indicates that transmembrane ephrin-B ligands may represent some of the crucial repulsive cues in the caudal somite. In vitro stripe assays have shown that ephrin-B1 and ephrin-B2 ligands repel motor axon outgrowth and neural crest migration (Wang and Anderson, 1997). To exert their guidance eects, ephrin-B1 and ephrin-B2 have to be presented nonuniformly, suggesting that the underlying mechanisms for the guidance of axons and of migrating cells may be similar. In a complementary in vivo approach, it was shown that misexpression of ephrin-B1 in rostral half-sclerotomes of whole trunk explants resulted in disorganization of neural crest cell movement and opened up the caudal somite to neural crest migration (Krull et al., 1997). Neural crest cells from the hindbrain also migrate in a segmental manner into the branchial arches to generate distinct sets of cartilage and bones of the face. Disruption of Eph receptorligand interactions, either by dominantnegative forms of Eph receptors, or by ectopic expression of ephrin-B2 ligand, leads to defects in branchial neural crest migration (Smith et al., 1997). It is not currently known whether ephrin-A ligands play a role in neural crest

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Ephrins

migration and motor axon outgrowth. At least two EphA receptors (EphA3 and EphA4) have been detected in subsets of spinal motor neurons.

Eph Receptor Signalling

Based on their biological functions in axon and cell targeting, signalling by Eph receptors is expected to provide a link to the machinery of the cell cytoskeleton (Bru ckner and Klein, 1998). Eph receptors share the common features of receptor tyrosine kinases. Upon ephrin ligand binding, receptor autophosphorylation is induced. In the case of Eph receptors this may involve the formation of larger receptor aggregates rather than simple dimerization, as assumed for other families of receptor tyrosine kinases. Tyrosine phosphorylation of the receptor thereby creates docking sites for signalling molecules that bind phosphotyrosine (PY) residues with their Srchomology-2 (SH2) or phosphotyrosine-binding (PTB) domains (Pawson and Scott, 1997; Holland et al., 1998). Two tyrosine (Y) residues in the juxtamembrane region, conserved in all Eph receptors, bind the SH2 domain protein p120RasGAP, which forms a complex with a tyrosine-phosphorylated form of p190RhoGAP, a negative regulator of the small guanosine triphosphatase (GTPase) Rho (Holland et al., 1997). These interactions are intriguing in light of the fact that the small GTPases of the Rho family, Cdc42, Rac and Rho, are key regulators of the actin cytoskeleton and thereby control the formation of lopodia, lamellipodia and stress bres. RasGap, upon stimulation of the EphB2 receptor, also forms a complex with inducibly tyrosine-phosphorylated p62dok, a pleckstrin-homology (PH) domain-containing protein that can provide docking sites for PY-binding proteins. Tyrosinephosphorylated p62dok associates with the SH2SH3 adaptor protein Nck, which was shown to play a functional role during axon guidance and fasciculation in the Drosophila visual system. One of the two Eph juxtamembrane autophosphorylation sites interacts with the nonreceptor tyrosine kinase Src or its relative Fyn (Ellis et al., 1996). Src family tyrosine kinases mediate mitogenic eects, but they are also involved in the organization of the cytoskeleton, as well as in cell scattering and morphological changes in epithelial cells. Activated forms of Src kinases have been implicated in the phosphorylation of various cellular proteins, such as paxillin, Fak and tensin, that are associated with integrinharbouring focal adhesions and with proteins such as p120 and b-catenin that are found in cadherin-containing adherens junctions. Another physiological substrate for Src is cortactin, an actin-binding protein implicated in growth factor signalling. Cortactin mediates crosslinking of lamentous (F-) actin into bundles and, interestingly,

this activity can be negatively regulated by Src-mediated phosphorylation of the protein. Recent experiments have emphasized the importance of ligand clustering for the signalling of Eph receptors. Only ephrin-B higher order oligomers, but not dimers, promote the assembly of endothelial cells into capillary-like structures and the attachment of P19 embryonic carcinoma cells through the activation of endogenous EphB receptors (Stein et al., 1998). Activated EphB receptors required an intact tyrosine residue near the C-terminus. High-level expression of mutant receptors, in which this tyrosine was mutated to phenylalanine, served as dominant-negative proteins that disrupted cell attachment responses and the recruitment of downstream eector proteins such as the low-molecular weight protein tyrosine phosphatase (LMW-PTP). It is believed that ligand oligomerization is an important regulatory mechanism to start EphB signalling. EphB-expressing cells may be able to discriminate between target cells on the basis of the degree of ligand clustering. Whether or not these mechanisms have an inuence on ligand signalling is currently not known.

Summary
Ephrins and Eph receptors have important roles in the formation of topographic projections and commissures in the vertebrate brain. In addition, they are involved in patterning events, axon fasciculation and cell migration. Ephrins may have to form higher order clusters to activate Eph receptor signalling. Transmembrane ephrin-B ligands have the potential to signal into the ligand-expressing cell after having contacted the corresponding Eph receptor on a neighbouring cell.

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