Brain Development
proper number of neurons can be gener-
ated in the neuroectoderm, otherwise all
cells become neurons (the so-called
rogenic phenotype
) after neural induction.
At later stages of
neural devel-
opment, Notch/Delta signaling is utilized
to control the cell type speciFcation in the
series of cell divisions. ±or example, af-
ter the sensory precursor cells are selected
from the epithelium, each of them should
produce four distinct cell types: a neuron,
glia (sheath), socket, and shaft (±ig. 9b).
As shown in ±ig. 9(b), Notch signaling,
together with Numb, seems to suppress
the glia as well as shaft cells to become
neuron and shaft cells. In vertebrate ner-
vous systems, the Notch/Delta signaling
pathway appears to be involved in deter-
regulated way; prospective primary neu-
rons expressing the ligand Delta inhibit
lateral cells expressing the receptor Notch
to further differentiate into neurons, re-
sulting in the stripe domains of neuron
production along the D–V axis of the neu-
ral plate/tube. In the mammalian cerebral
cortex, similar mechanisms help generate
cortical granule cells (±ig. 9c). Using time
lapse imaging, it has been demonstrated
that a radial glial cell (ependymal cell) in
the cortical ventricular zone divides to pro-
duce one neuron and a cell maintaining
the radial glial cell characters (±ig. 9c). In
this process, the cells that get into the
neuronal lineage have been shown to in-
herit the Numb protein from the radial
glial cells/stem cells via asymmetric cell
divisions, repressing the receptor Notch
activity to Fnally be determined as neu-
ronal (±ig. 9c). PNS gangliogenesis is also
shown to be dependent on this signaling
mechanism, controlling the neuron/glia
ratio in the dorsal root ganglia.
As I described earlier, early patterning
plate/tube along the A–P and D–V axes
via a series of complex actions of secreted
molecules such as BMP, Shh, WNT, ±G±,
RA, and so on. This directly helps in
generating various sets of neurons, as a
distinct address in the neural plate/tube
per se
restricts the deFnitive number of
transcription factors able to be turned
on. Besides the Shh dependent neuronal
generation machinery along the D–V axis
of the spinal cord, which I have already
described in detail earlier (see Sect. 2.1;
±ig. 4),
genes have been shown to
play a role in generating distinct sets of
neurons along the A–P axis. ±or instance,
it has been demonstrated that inactivation
of members of the
gene clusters expressed in the spinal
motor neurons leads to alterations in the
motor innervation of speciFc muscles in
the limb. Additionally, in the developing
Fig. 9
Mechanisms involved in neurogenesis during development (a) Cell intrinsic machineries play
crucial roles in
neurogenesis as well as gliogenesis. GMC, ganglion mother cell; Pon,
partner of numb; pros, Prospero. (b)Roles of Numb and Notch signaling in the
organ precursors (SOPs). (c)Neurogenesis in the mouse cerebral cortex. A radial glial cell (a stem
cell) divided asymmetrically within the ventricular zone (VZ) produce a radial glial cell (Numb
negative) and a radial neuron (Numb positive). The latter will migrate radially along the long process
of radial glial cells, differentiate into a neuron in the intermediate zone (IZ), and Fnally settle within
the cortical plate (CP). (d) Notch/Delta signaling machineries. Notch with 36 EG±-like repeats can
bind to Delta with 9 EG±-like repeats expressed by a neighboring cell, resulting in the release of
Notch cytoplasmic domain into the nucleus. The cytoplasmic tail can directly bind to DNA and
transactivate target genes.
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