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studies have shown that it is not the only factor with
this capability. As we noted earlier in this section,
retinoic acid is also secreted from the mesoderm and
has effects in the neural tube, specifically in the devel-
oping hindbrain. Studies by Novitch et al. (2003) have
found that RA, along with FGF, can almost completely
replace the Shh signal and restore ventral development
to tissue without any detectable Shh. This result, along
with the finding that elimination of a downstream
effector of Shh signaling, the Gli transcription factor,
from mice can nearly completely rescue ventral devel-
opment in the Shh -deficient mice (Litingtung and
Chiang, 2000), indicates that Shh may be only one of
several redundant molecular signals that pattern the
ventral axis of the neural tube. As we saw for neural
induction, a multiplicity of partly overlapping signals
and transcription factors are responsible for the cellu-
lar diversity we know as pattern in the nervous system.
enchyme in the head, including that which forms the
visceral skeleton and the bones of the skull, is derived
from neural crest. The neurons and glia of several
cranial ganglia, like the trigeminal sensory ganglia, the
vestibulo-cochlear ganglia, and the autonomic ganglia
in the head, are also derived largely from the progeny
of the neural crest as well as from the cranial placodes.
These placodes that give rise to the nose, the lens of the
eye, the otic vesicle, and components of cranial sensory
ganglia form a ring around the anterior edge of the
neural plate and may be considered as a kind of ante-
rior extension of the neural crest.
Because of the extensive migration of the neural
crest cells, and the great diversity of the tissues and cell
types to which neural crest cells can contribute, the
neural crest has been studied extensively as a model
for these aspects of nervous system development. In
the next sections we will review what is known about
the origin of the neural crest and the factors that control
the initial aspects of its differentiation. Chapter 3 will
detail additional studies of the factors that control
neural crest migration, and Chapter 4 will deal with the
cellular determination of various crest derivatives.
Classically, the neural crest has been thought to
arise from the cells that form at the fusion of the neural
folds when they become the neural tube. Vogt, using
vital dyes to fate-map the different parts of the
amphibian embryo, found that most of the neural crest
forms from a narrow stripe of ectodermal cells at the
junction between the neural plate and the epidermis.
Subsequent studies using more sophisticated tech-
niques have expanded this view. Le Douarin and her
colleagues have extensively used the chick-quail
chimera system described above to track the fate of the
neural crest that arises from the different regions along
the neuraxis to show the different types of tissues that
are generated from different rostral-caudal regions
(Figure 2.26). Bronner-Fraser and Fraser (1991) used
single-cell injections to track the lineages of individual
crest cells prior to their migration. The injected cells
went on to divide, and they retained their lineage
marker for several cell divisions. Many of the labeled
cells went on to contribute to the tissues described
above as the normal neural crest derivatives; however,
some of the labeled cells that contributed to the neural
crest also had progeny that populated the neural tube
and the epidermis. Thus, although most of the cells in
the neural crest field at the neural plate stage of devel-
opment normally develop into neural crest, they are
not restricted to this lineage. In addition, although in
many embryos, the neural crest develops at the fusion
of the neural folds, there are regions of the neuraxis in
some species that do not form by the rolling of the
neural plate. For example, in the fish, the neural tube
The experiments of Harrison and others showed
that removal of the notochord resulted in a neural tube
without much dorso-ventral polarity. This implies that
the dorsal neural tube is in some way the default con-
dition, whereas the ventral structures require an addi-
tional signal to develop their fates. However, in the last
few years it has become apparent that the dorsal
neural tube also requires signals for its appropriate
development. Before the neural tube closes, the future
dorsal neural tube is continuous with the adjacent
ectodermal cells. As the dorsal neural tube closes, the
neural crest forms at the point of fusion of the neural
tube margins. Thus, the neural crest is, in some sense,
the most dorsal derivative of the neural tube, and has
often been used as an indicator of dorsal differentia-
tion. In addition, several genes specifically expressed
in the dorsal neural tube at these early stages of devel-
opment are critical for the specification of neural crest
(e.g., slug and snail ).
After extensive migration, the neural crest gives rise
to an array of different tissues. In the trunk, the neural
crest gives rise to the cells of the peripheral nervous
system, including the neurons and glia of the sensory
and autonomic ganglia, the Schwann cells surrounding
all peripheral nerves, and the neurons of the gastric
mucosal plexus. Several other cell types, including
pigment cells, chromatophores, and smooth muscle
cells, arise from the trunk neural crest. Neural crest also
forms in the cranial regions, and here it contributes to
most of the structures in the head. Most of the mes-
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