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BOX
NEURAL CREST MIGRATION
genes as it migrates from the neural tube, and thus has a
unique identity. This unique identity can be demonstrated
by transplantation experiments where crest from one
rhombomere is transplanted to the region of another, and
its migration and further development are monitored
(Noden, 1983). Crest cells that would normally populate
the third arch were excised and replaced with first arch
crest cells. The transplanted crest cells migrated into the
third arch, but instead of making neck cartilage, they
formed beaklike projections from the neck and a complete,
duplicate first arch skeletal system in their new location.
Thus, it appears that the patterning of branchial arch
skeletal and connective tissues is an intrinsic property of
the cells of the neural crest prior to their emigration from
the neural tube. Although they can use the same cues to
migrate through the branchial arches, they will differenti-
ate in accord with the Hox code specific for their position
or origin.
m
r1
r2
r3
r4
r5
r6
A1
r7
A2
A3
therefore it is possible that the gradual lengthening
of the G1-phase of the cell cycle in neural progenitor
cells within the CNS (above) is due to an increasing
dependence on these factors for progression through
the cell cycle as development proceeds. The factors
that have been shown to act as mitogens for the
mitotically active cells in the progenitor cells of the
vertebrate CNS are primarily those peptides that act
on receptor tyrosine kinases, including FGFs, TGF-
alpha, EGF, and insulin-like growth factors. However,
there are many other types of signaling molecules that
act on progenitor cells in the nervous system and also
play a role in their proliferation. Sonic hedgehog and
members of the Wnt protein family are examples of
molecules that were involved in patterning the
nervous system (reviewed in Chapter 2), but are also
critical for the regulation of progenitor proliferation at
later stages of brain development.
The identification of mitogenic factors for nervous
system progenitor cells has relied on cell culture
studies. Neural progenitor cells can be isolated from the
developing brain by dissociating the cells with
enzymes and putting them in culture dishes. The pro-
genitor cells in the culture dishes will divide and make
both additional progenitor cells and differentiated
neurons (Figure 3.9). Some of the early studies tested
many of the growth factors that stimulated prolifera-
tion of cells in other tissues and found that some of the
best mitogens for the progenitor cells of the nervous
system were those that stimulated fibroblast cells (FGF)
or skin cells (EGF). Progenitor cells express receptors
for the various mitogenic factors, and depending on
their location and stage of development, they are more
responsive to one mitogen or another. Mitogenic factors
like EGF and FGF bind to receptors of the tyrosine
kinase signaling pathway to stimulate cell division by
the upregulation of the S-phase cyclins, such as cyclinD .
Since cyclinD expression will stimulate the cells to enter
the S-phase, the regulation of cyclinD is a direct mecha-
nism to control cell-cycle entry by a growth factor. In
this way, the extracellular signals are integrated with
the intrinsic cell cycle regulation machinery.
A factor first encountered in the context of pattern-
ing the nervous system (Chapter 2), sonic hedgehog , is
also a key mitogen for nervous system progenitors.
The Shh mitogenic pathway is important in many
regions of the brain, particularly those of the dorsal
brain (Figure 3.10). The way in which Shh acts in neu-
rogenesis demonstrates the way in which differenti-
ated neurons can feed back on the progenitors to
maintain their proliferation and ensure that the correct
number of neurons is generated during development.
Although the Shh mitogenic pathway is used in
many areas of the developing brain, the genesis of
granule neurons in the cerebellum is a good example
(Wechsler-Reya and Scott, 1999). The cerebellum is
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