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3
-null m utant fetuses develop cleft palate so that
all TG F-
3
-null pups die shortly after birth (Proetzel
et al., 1995). The TG F-
3
knockout m ouse is char-
acterised by appearing to have no other m orpho-
logical anom alies (excepting the lung). TG F-
1
knockout m ice, how ever, do not develop cleft
palate (Shull et al., 1992; Kulkarni et al., 1993) and
B. J . Moxham
68
Figure 19. The m edial edge epithelia of palatal shelves labelled
im m unocytochem ically for type IX collagen at a tim e
w hen m edial edge epithelial differentiation occurs as
determ ined by recom bination experim ents. x 500.
Courtesy of Professor M .W .J. Ferguson.
cleft palate, along w ith m any other types of
abnorm alities, is observed (but at low er incidence
rates) in TG F-
2
knockout m ice (Sanford et al.,
1997). That TG F-
3
plays an im portant role in
palatal shelf fusion is also show n by the fact that
palate fusion fails to occur in vitrow hen the activ-
ity of TG F-
3
is inhibited by antisense oligonu-
cleotide or by neutralising antibody (Brunet et al.,
1995). M ore recently, Taya et al. (1999) reported
that m utation of the TG F-
3
gene results in cleft
palate form ation and that, w hen palates from
transgenic m ice w ith TG F-
3
deletions are grow n
in organ culture such that shelves w ere placed in
hom ologous (+/+ vs +/+, -/- vs -/-, +/- vs +/-) or
heterologous (+/+ vs -/-, +/- vs -/-, +/+ vs +/-)
paired com binations, pairs of -/- and -/- shelves
failed to fuse w hile pairs of +/+ and =/+ shelves
show ed com plete disappearance of the M ES
w hereas -/- and +/+ shelves retained som e rem -
nants of the M ES. They also studied the ability of
TG F-
3
fam ily m em bers to rescue the fusion
betw een -/- and -/- palatal shelves in vitro by
adding to the culture m edium recom binant hum an
TG F-
1
, porcine TG F-
2
, recom binant hum an
TG F-
3
, recom binant hum an activin, or porcine
inhibin. It w as reported that, for untreated organ
culture -/- palate pairs that w ould be expected to
show com plete failure to fuse, TG F-
3
treatm ent
induced com plete palatal fusion w hereas TG F-
1
or TG F-
2
produced near norm al fusion and
activin and inhibin had no effect. The m echanism
w hereby TG F-
3
rescued the fusion w as claim ed
to be related to the appearance of filopodia-like
process on the surface of the M ES cells that are
coated w ith m aterial resem bling proteoglycan.
O nce fusion is com plete, the hard palate ossi-
fies intram em branously from four centres of ossi-
fication, one in each developing m axilla and one
in each developing palatine bone (Sperber, 2001;
Berkovitz et al., 2002; M eikle, 2002). The m axil-
lary ossification centre lies above the developing
deciduous canine tooth germ and appears in the
eighth w eek of developm ent. The palatine centres
of ossification are situated in the region form ing
the future perpendicular plate and appear in the
eighth w eek of developm ent. Incom plete ossifica-
tion of the palate from these centres defines the
m edian and transverse palatine sutures. There
does not appear to be a separate centre of ossifi-
cation for the prim ary palate in M an (in other
species there being a separate prem axilla). Fig-
ure 20 provides a coronal section through the
developing hard palate to show early ossification.
CLIN ICAL CO N SID ERATIO N S
M alform ations of palatogenesis m ay result in the
appearance of clefts (Sperber, 2001; Berkovitz et
The development of the palate a brief review
69
Figure 20. Coronal section through the developing hard palate show ing early ossification. A = developing body of m axilla; B = bone extend-
ing from body of m axilla into palate; C = nasal cavity. (M assons trichrom e). x 160.
C
A
B
al., 2002; M eikle, 2002). Clefts of the palate, like
those of the lip, are m ultifactorial m alform ations,
involving both genetic (polygenic) and environ-
m ental factors. Clefts m ay result from distur-
bances of any of the processes involved during
palatogenesis, i.e. from defective palatal shelf
grow th (e.g. Abbott et al., 1990); delayed shelf
elevation or failure of elevation (e.g. Ferguson,
1981a); defective shelf fusion or lack of degen-
eration of the M ES; or failure of m esenchym al
consolidation and/or differentiation (e.g. Abbott
and Birnbaum , 1989).
The m ildest form of cleft is that affecting the
uvula, such a disturbance occurring relatively late
in the process of palatal m alfusion. D isturbances
occurring during the early phases of palatal
fusion can result in a m ore extensive cleft involv-
ing m ost of the secondary palate. Should the cleft
involve the prim ary palate, it m ay extend to the
right and/or left of the incisive foram en to
include the alveolus, passing betw een the lateral
incisor and canine teeth. Cleft palate m ay be
associated w ith cleft lip, though the tw o con-
ditions are independently determ ined. D ental
m alform ations are com m only associated w ith a
cleft involving the alveolus. A subm ucous cleft
describes a condition w here the palatal m ucosa is
intact, but the bone/m usculature of the palate is
deficient beneath the m ucosa. Less problem atic
than clefts (but m ore com m on) is the retention of
epithelial rem nants in the m idline that eventually
becom e cystic.
H ypotheses to explain the m echanism s
responsible for cleft palate form ation range from
genetic predisposition (e.g. Bonner and Slavkin,
1975) to the adm inistration of teratogens (e.g.
Fraser and Fainstat, 1951). Ferguson (1981b) has
also proposed that the expression of a cleft
palate is a m anifestation of phylogeny - birds
develop a physiological cleft and the oral and
nasal cavities are not separated (e.g. Shah and
Craw ford, 1980). Recent research indicates that
retinoids in excess have a teratogenic effect, pro-
ducing clefts of the palate and the abnorm al
appearance of islandsof cartilage in the m es-
enchym e (Em m anouil-N ikoloussi et al., 1999;
Em m anouil-N ikoloussi et al., 2000). M ore recent-
ly, w ork by G unston, M oxham and Em m anouil-
N ikoloussi (unpublished data) show s that all-
trans retinoic acid (RA) is the m ost teratogenic
isom er of RA in term s of rat palatal abnorm alities,
that the tim e of adm inistration of RA is m ore crit-
ical than dose, but that im m unohistochem ical
labelling for cartilage ECM m olecules fails to
detect ectopic cartilage w ithin the palates.
Ectopic localization of Sonic hedgehog protein
(Shh) in the developing rostral neural tube is also
associated w ith craniofacial defects (N asrallah
and G olden, 2001). This is thought to be due to
disruption in norm al genes expression patterns
(e.g. wnt-3a, wnt-4, Pax-6, HNF-3( and Ptc).
Studies using transgenic m ice suggest that
m any hom eobox genes and transcription factors
are involved in palatogenesis. For exam ple,
Satokata and M aas (1994) have highlighted the
possible significance of Msx1 and W inograd et
al. (1997) of Msx2. Tissier-Seta et al. (1995) have
suggested a role for Barx 1. G endron-M aguire et
al. (1993) and Rijli et al. (1993) suggest that
H oxa2 is im portant and M artin et al. (1995) have
im plicated Mhox. Peters et al. (1997) have deter-
m ined a role for Pax9 and M o et al. (1997) have
reported on the significance of Dli and Dli3.
Finally, Takihara et al. (1997) suggest that there
is expression of rae28 during palatogenesis and
Takagi et al. (1998) deltaEF1. Additionally, m any
cytokines (and their receptors) are also involved
in palate developm ent. For exam ple, TG F-
alpha/EG F receptors, TG F-
2
, and TG F-
3
have
im portant functions (M iettinen et al., 1999; San-
ford et al., 1997; Proetzel et al., 1995; K aartinen
et al., 1995; see also above). Furtherm ore, im por-
tance has also been claim ed for activin-A,
activin-receptor type II and follistatin (M atzuk et
al., 1995a, b, c). Lohnes et al. (1993, 1994) have
show n a role for retinoic acid receptor gam m a
during palate developm ent and K urihara et al.
(1994) have reported on endothelin. O rioli et al.
(1996) have suggested an involvem ent of
sek4/nuk1.
ACK N O W LED G EM EN TS
I w ould like to thank all m y colleagues w ho, at
the U niversities of Bristol, Cardiff and Thessa-
loniki, have collaborated w ith m e in the study of
palatogenesis, nam ely: D r. G .D . Singh, D r. W .
M cLean, D r. R. H all, D r. S. Thom as, M s L. H ud-
son, M s E. G unston, Prof. G . Em bery, D r. R.J.
W addington, D r. M .S. Langley, D r. E-N .
Em m anouil-N ikoloussi. M any thanks for your
hard w ork and inspiration. I w ould also like to
thank St. G eorges U niversity (G renada), and
especially Prof. R. Jordan, for providing m e w ith
facilities necessary to com plete this paper.
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