1.3 Neural Development and Neurogenesis
25
The Cerebral Cortex
Recent evidence suggests that forebrain development also
depends on inductive signals and patterning genes as observed
in more caudal neural structures. In the embryo, the dorsal fore-
brain structures include the hippocampus medially, the cerebral
cortex dorsolaterally, and the entorhinal cortex ventrolaterally,
whereas in basal forebrain, the globus pallidus lies medially and
the striatum laterally. On the basis of gene expression and mor-
phological criteria, it has been hypothesized that the forebrain is
divided into a checkerboard-like grid pattern of domains gener-
ated by the intersection of longitudinal columns and transverse
segments, perpendicular to the longitudinal axis. The columns
and segments (prosomeres) exhibit restricted expression of
patterning genes, allowing for unique combinations of fac-
tors within each embryonic subdivision. Many of these genes,
including
Hnf3
b
, Emx2, Pax6,
and
Dlx2,
are first expressed even
before neurulation in the neural plate and are then maintained,
providing the “protomap” determinants of the VZ described
earlier. As in spinal cord, initial forebrain gene expression
is influenced by a similar array of signaling center soluble
factors—Shh, BMP, and retinoic acid. As the telencephalic ves-
icles form, signaling centers localize to the edges of the cortex.
In the dorsal midline there is the anterior neural ridge, an ante-
rior cranial mesenchyme secreting FGF8, the roof plate, and, at
the junction of the roof plate with the telencephalic vesicle, the
cortical hem (Fig. 1.3-6). Other factors originate laterally from
the dorsal–ventral forebrain junction, as well as from basal fore-
brain structures themselves.
Do molecular studies identify how different cortical regions interact
with thalamic neurons to establish specific functional modalities, such
as vision and sensation? And once regional identity is established, can
it be modified by later developmental events? It has been proposed that
initially there are no functional distinctions in the cortex but that they
are induced by the ingrowth of extrinsic thalamic axons, which con-
vey positional and functional specifications, the so-called “protocortex
model.”However, in contrast, the abundant molecular evidence provided
earlier suggests that intrinsic differences are established early in the neu-
roepithelium by molecular determinants that regulate areal specifica-
tion, including the targeting of thalamic axons, termed the “protomap”
model. The foregoing mutants now provide experimental tests of these
two alternative models and indicate that neither model is completely
correct. Although there is early molecular regionalization of the cortex,
the initial targeting of thalamic axons to the cortex is independent of
these molecular differences. In the rodent, thalamic afferents first target
to their usual cortical regions prenatally in the late embryo. However,
once thalamic afferents reach the cortex, which occurs several days
after birth, interactions of thalamic axon branches with local regional
cues leads to modifications of initial outgrowth and the establishment
of connections that conform to areal molecular identities. Furthermore,
the developing cortex exhibits a remarkable and unexpected level of
Figure 1.3-5
Patterning genes in the spinal cord.
A.
Diagram illustrating the localization of gene expression in the developing “trunk.” Rhombomere
boundaries are specified by specific combinations of transcription factors. (Modified from Darnell, 2005.)
B.
Morphogen induction of
spinal cord cell fate. Dorsoventral gradients of sonic hedgehog (Shh) and bone morphogenetic protein (BMP) induce expression of several
position identity genes. Combinatorial effects of these factors establish progenitor domains and result in the expression of specific down-
stream molecular markers. D, dorsal neurons; V, ventral neurons. (From Sadock BJ, Sadock VA, Ruiz P.
Kaplan & Sadock’s Comprehensive
Textbook of Psychiatry.
9
th
ed. Philadelphia: Lippincott Williams & Wilkins; 2009:51.)
