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A
B
astrocyte
progenitors
neural
tube
oligo-
dendrocyte
blood
vessels
astrocyte
axons/
dendrites
oligodendrocyte
progenitors
neurons
C
Astrocytes
ventricular layer
PDGF
NT-3
neural
progenitor
glial
progenitor
stem cell
Prolifera tion
Oligodendrocyte
p27Kip1
OPCs
D
Stem cell
produces neurons
Stem cell
produces glia
Olig1 Nrgn2
Olig1
Nrgn2
Olig1 Nrgn2
expression
Olig1 Nkx2.2
expression
Time
Olig1
Nkx2.2
Switch
point
Nkx2.2
Nkx2.2
FIGURE 4.27 Glial cell development in vertebrates. A. Two main types of glial cells, oligodendrocytes
and astrocytes, are formed in the neural tube. Astrocyte progenitors are distributed at all levels, whereas
oligodendrocyte progenitors derive from the ventral neural tube. B. Oligodendrocytes form processes that
wrap around axons and give rise to the myelin sheath. Astrocyte processes connect to capillaries and neu-
rites. Glial progenitors and neural progenitors are derived from the same pool of stem cells that divide in the
ventricular layer of the developing neural tube (bottom of B). At early stages, a stem cell generates neuro-
blasts. Later it undergoes a specific asymmetric division (the “switch point”), at which it changes from making
neurons to making glia. C. In a culture system, optic nerve-derived oligodendrocyte progenitors (OPCs)
depend on secreted signals from astrocytes. PDGF and NT-3 maintain OPC proliferation. In the absence of
these factors, OPCs stop dividing and differentiate. The internal clock that determines when an OPC stops
dividing depends on the level of the p27Kip1 protein, a cell cycle inhibitor that builds up over time and finally
drives the cells to exit the cell cycle. D. The dorsally shifting expression of Nkx2.2 causes a change in gene
expression in the progenitor cells driving the switch point (see text).
common themes such as successive restrictions in
potency and potential as progenitor cells develop and
divide. There is immense variation in the role of
lineage versus environment in neuronal determina-
tion, with the general rule that invertebrates are more
dominated by lineage mechanisms, while vertebrates
are more dominated by diffusible signals and cellular
interactions. Each determination pathway, however,
usually brings its own mix of lineage-dependent and
lineage-independent mechanisms. Of the transcription
factors, bHLH factors of the proneural class help tell
cells to become neurons and are antagonized by the
Notch pathway which favors late differentiation of
glia. Homeobox and paired domain transcription
factors are often used to restrict neurons to certain
broad classes linked to their position or coordinates of
origin. Finally, POU, LIM, and ETS domain transcrip-
tion factors may restrict cellular phenotypes even
further. Of the signaling molecules, we find a particu-
larly important role for the Notch pathway, but also
important roles for BMPs, FGFs, and Hedgehog pro-
teins. The last phases of determination involve each
neuron interacting with its synaptic targets, which
may provide the final differentiative signals for the
maturing neuron. At the end of this process, the
neuron becomes an individual cell with its own bio-
chemical and morphological properties and its unique
set of synaptic inputs and outputs.
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