104
Brain Development
posterior expression border of transcrip-
tion factor Pax6 (Fig. 6b). The anterior
expression border of another paired do-
main containing transcription factor Pax2
as well as a homeodomain-containing
transcription factor Engrailed1 (En1) com-
plementarily delineates the Pax6 negative
domain in the neural plate (Fig. 6b). It has
also been reported that the posterior ex-
pression border of the Otx2 transcription
factor as well as the anterior border of
Gbx2 coincides with the posterior limit of
the future midbrain (Fig. 6b). Repressive
interactions among such transcription fac-
tors have been suggested as being required
for the establishment and maintenance
of the mutually exclusive expression of
these transcription factors at the future
forebrain/midbrain boundary (FMB) and
midbrain/hindbrain boundary (MHB). Ec-
topic Gbx2 expression in the midbrain
using the
in vivo
electroporation (EP)
method (see Sect. 7), for instance, down-
regulates Otx expression only within the
cells expressing ectopic Gbx2. While the
FMB is a compartment boundary at the
mouse neural plate stages, the midbrain
and hindbrain cells are able to freely in-
t
e
rm
i
x
.H
en
c
e
,t
h
em
u
t
u
a
l
l
yr
e
p
r
e
s
s
i
v
e
interactions between Otx2 and Gbx2 are
very important to precisely de±ne the MHB
during early development.
The Otx2/Gbx2 expression border then
generates the anatomically identi±able
boundary between the midbrain and hind-
brain called the
isthmus
, which harbors
the local organizing activity for midbrain
A–P patterning. For instance, if this re-
gion is grafted into the forebrain region,
the entire structure of the posterior mid-
brain would be induced with its mirror
image in the anterior midbrain and the
topological innervations of the retinal neu-
rons would be bifurcated (Fig. 8a). Wnt1
and Fgf8 secreted proteins appear to be the
candidate signals for midbrain patterning.
Wnt1 mutant mice lack the midbrain, and
Fgf8 expressing cells or beads can mimic
organizer activity (Fig. 8a). In addition,
Wnt1 and Fgf8 signaling pathways form
a regulatory loop that controls homeobox-
containing transcription factors, such as
En1/2, to establish and maintain the MHB
o
rgan
ize
raswe
l
lastheen
t
i
rem
idb
ra
in
structure (Fig. 8a).
2.2.3
Forebrain Specifcation
The forebrain (prosencephalon), which is
the most anterior portion of the CNS, gives
rise to a variety of tissues during develop-
ment including the eyes, telencephalon,
and diencephalon. Within this area, mam-
mals have acquired a six-layered architec-
ture of cells named the neocortex, and the
region has evolved, especially in human be-
ings, for total cognitive association as well
as linguistic communication. In the de-
veloping forebrain, segmental structures
speci±cally termed
prosomeres
are known
to appear (Fig. 6c). In chicken and mouse
embryos, at least six units (p1–p6) are
anatomically recognizable, and using the
dye-labeling method, some of their bound-
aries have been shown to stand as limits of
cell lineage restrictions just like the rhom-
bomeres in the hindbrain. Several axon
tracts seem to coincide with the prosomere
boundaries, suggesting that prosomeres
might also provide the basic framework
for forebrain structures. Then, how are
such prosomeres formed and maintained
during development?
In the early chicken neural plate stage,
mutual repression between the transcrip-
tion factors, Irx3 and Six3, was found to
±rst set a boundary within the future fore-
brain, which later coincided with the p2/3
boundary speci±cally called the
zona limi-
tans interthalamica
(ZLI) (Fig. 6b). A recent
study using the organ culture system has
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