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FGFs
Neurotrophins
A
Retina
FGFR
Trk
Type-2 astrocyte
Mapk
Retinal
ganglion
cells
Neuron
Optic nerve
Astrocyte
Blood vessel
pro-neural
bHLH TFs
Axon
Type-1
astrocyte
Node of
Ranvier
Id1/3
Hes5
Oligodendrocyte
smad
SuH
STAT
B
EGFR
CNTFR
BMPRIb
Notch
PDGF
NT-3
EGF CNTF BMP Delta
FIGURE 3.11 Various mitogenic factors control proliferation of
the different types of progenitors in the nervous system. Neurogen-
esis and gliogenesis are regulated by many growth factors, and these
are summarized in the figure. FGF2 and Neurotrophin3 promote pro-
genitor cells isolated from brain to develop primarily as neurons,
likely through the increase in expression of proneural bHLH genes,
such as NeuroD1 , EGF, and CNTF, which cause the progenitor cells
to develop as astrocytes, and at least for CNTF this is known to work
through the activation of the STAT transcription factor, which binds
to the promoter of the glial-specific gene, GFAP. BMPs can synergize
with CNTF to promote glial development, partly through the STAT
pathway and partly through a direct inhibition of the proneural
genes via the Hes pathway. Notch activation also activates the Hes
pathway to promote gliogenesis and inhibit neurogenesis.
Type-1
astrocyte
Oligodendrocyte
?
Type-2 astrocytes
?
O2-A progenitors
CNTF
FIGURE 3.12 Glial diversity in the optic nerve. A. The optic
nerve has three different types of glia, type 1 and type 2 astrocytes
and oligodendrocytes. B. Culture studies show that type 1 astrocytes
secrete PDGF and NT-3 , which causes O2-A progenitors to divide.
After a certain number of divisions, O2-A progenitors are timed to
differentiate as oligodendrocytes or type 2 astrocytes if they are
exposed to CNTF and other (?) factors. (Adapted from Harris and
Hartenstein, 1999)
type of cell, the O2A progenitor (for O ligodendrocyte,
and type 2A strocyte), can produce either astrocytes or
oligodendrocytes, depending on the culture conditions
(Raff et al., 1983). These O2A progenitor cells thus
depend on signals to direct their differentiation. Mul-
tiple signals cause these cells to proliferate and
develop as oligodendrocytes, including many of the
same factors mentioned above: PDGF, NT3, and IGF-
1. These factors are all produced by the astrocytes of
the optic nerve, and PDGF is also produced by the
retinal ganglion cells and present in their axons. In
addition to these growth factors, the electrical activity
of the axons in the optic nerve is also important for
oligo progenitor cell proliferation; blocking electrical
activity results in a decline in the number of oligo-
dendrocytes in the nerve (see Barres and Raff, 1994, for
review). Tethering the production of oligodendrocytes
to the axons in the nerve may provide a way to ensure
that sufficient oligodendrocytes are produced to prop-
erly myelinate all the axons.
Another critical genetic pathway that can control
glial versus neuronal fate is the Notch pathway. The
Notch pathway regulates lateral inhibition of cell fate
during the very early stages of brain development
(Chapter 1). At the early stages of neural development,
activation of the Notch pathway prevents epidermal
cells from becoming neuroblasts in Drosophila by
down-regulating the expression of the proneural genes
achaete and scute . Similarly, overexpression of the
proneural genes, either in flies or in frog embryos,
causes ectopic neurons to form from the epidermis.
Studies over the past 10 years have also demonstrated
that the proneural genes continue to be expressed in
the vertebrate nervous system throughout develop-
ment. The neural progenitor cells express several
proneural genes, including NeuroD1 , Neurogenin , and
Mash1 (Figure 3.13). The expression of these genes
in part determines whether a progenitor will produce
a neuron or a glial cell. If the Notch pathway is acti-
vated, the progenitors primarily generate astrocytes;
however, if the proneural genes are overexpressed in
the progenitor cells, they are biased to generate more
neurons than they normally would (Figure 3.14). Thus,
the proneural genes function in both the initial forma-
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