98
Brain Development
may therefore be required to prevent the
intermingling of cells between the alar and
basal plates. Overexpression of F-cadherin
in the frog neural tube indeed resulted
in the abnormal intermixing of cells in
the neural tube. Chicken cadherin-7, most
homologous to frog F-cadherin, further
delineates the sulcus limitans, suggesting
a conserved role for cadherins in main-
taining this important boundary between
the alar and basal plates during evolution
(Fig. 5c).
Curiously, in the process of neurula-
tion, the expression of cadherin subclasses
is dynamically regulated. In chicken em-
bryos, for instance, the neuroectoderm
loses E-cadherin expression and begins to
express N-cadherin (Fig. 5c). Cells at the
neural ridge then lose N-cadherin expres-
sion and begin to express cadherin-6B,
while the emigrating neural crest cells
switch off cadherin-6B expression and
acquire cadherin-7 expression (Fig. 5c).
These serial switches of cadherin sub-
classes during development are crucial,
as ectopic expression of N-cadherin in the
frog embryo causes abnormal segregation
between the ectoderm and neural tube.
Overexpression of N-cadherin or cadherin-
7inth
ech
i
ck
enn
eu
r
a
ltub
ei
sfu
r
th
e
r
revealed to result in the deterioration of
neural crest cell emigration, indicating
that the spatiotemporal expression pat-
tern of cadherin is important for normal
development. The repressive transcription
factor, Slug/Snail, is known to be involved
in epithelial–mesenchymal transition pro-
cesses by downregulating E-cadherin ex-
pressions
in vitro
.Th
istypeo
fregu
la
t
ion
might control emigrations of neural crest
cells
in vivo
, as Slug/Snail expression de-
lineates the neural fold during neural crest
emigrations. Yet, cadherin genes are huge
(
∼
200 kbp) with large introns, and the
transcriptional machineries required for
the spatiotemporary restricted expression
of cadherins has been poorly investigated.
2.2
A–P Patterning in the Neural Plate/Tube
It is known that tissues surrounding the
future neuroectoderm at the gastrulation
stage help establish A–P patterning in
neural tissue. As I already mentioned
earlier, Nieuwkoop proposed a two-step
model in which an early activating sig-
nal has a role in inducing neural tissue
with an anterior character (i.e. forebrain).
Subsequently, a second posteriorizing or
transforming signal converts some of the
posterior neural tissues into an even more
posterior character (i.e. hindbrain and
spinal cord). Supporting this model, dis-
tinct tissues have been shown to induce
different axial characters. For instance, in
mice, it has been demonstrated that the
combined action of the AVE and the node-
derived axial mesoderm (prechordal plate)
was important to represent anterior neu-
ral characters (Fig. 1c). Various signaling
molecules required to establish the ante-
rior character have indeed been identi±ed.
For example, secreted molecules such as
Nogg
inandChord
inhavebeenshownto
induce anterior characters as the gene tar-
geting mice have severe defects only in
the anterior structures. Another secreted
molecule, Cripto with a cysteine rich and
EGF-like motif has further been shown
to be a crucial morphogen organizing the
mouse A–P axis (refer to Fig. 1c and the
legend). Regarding the posteriorizing sig-
nals, retinoids, Wnt, and FGF signaling
have been implicated as the candidates.
For instance, explants from the frog ante-
rior neural plate were shown to acquire the
posterior identity when treated with FGF.
Additional mechanisms must be involved
in the posteriorization, as a simple block of
