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The neural crest exemplifies the migratory process in
embryology; no other tissue undergoes such extensive
migration during development as the cells of the neural
crest. As noted previously, the neural crest is a collection
of cells that emerges from the dorsal margin of the neural
tube, where it intersects with the ectoderm. Although the
neural crest was first described by His in the chick embryo
in 1868, the migration of the cells of the neural crest was
first demonstrated by Detwiler (1937) by labeling the pre-
migratory cells with vital dye. The neural crest from the
trunk takes two basic routes (Weston, 1963) from the
neural tube: the ventral stream, along which the cells that
will form the sensory, enteric and autonomic ganglia
follow, and the dorsal or lateral stream, in which the cells
that will form the pigment cells in the epidermis predom-
inate (Figure). The route that cells take is to some degree
determined by the environment in which they find them-
selves. There are differences in the types of cells that dif-
ferentiate from the neural crest at different points along
the anterior-posterior axis of the embryo. For example,
neural crest from the most anterior part of the developing
spinal cord migrates into the gut to form the enteric
nervous system, while neural crest from somewhat more
caudal levels of the spinal cord never migrates in to the
gut, but instead collects near the aorta and forms the sym-
pathetic ganglion chain. Transplantation of neural crest
cells from anterior (enteric ganglion forming) levels of the
embryo to more posterior regions results in the anterior
crest cells following the posterior pathways and making
sympathetic neurons instead of enteric neurons (LeDouarin
et al., 1975; LeDouarin, 2004).
What guides these cells to their proper locations in the
embryo? Both permissive and repulsive cues, similar to
those that guide growing axons (see Chapter 5), direct the
neural crest through these two main routes. Several large
extracellular glycoproteins and sulfated proteoglycans
have been shown to be critical for the migration of many
different types of cells. Two of these molecules, laminin
and fibronectin, are known to support the migration of
neural crest cells when the cells are dissociated from
the embryo and plated onto tissue culture dishes. The
receptors for these extracellular matrix molecules, het-
erodimers of integrin proteins, are expressed by the
migrating neural crest cells, and perturbation of these
receptors also inhibits neural crest migration. If either b1-
integrin, or its heterodimeric partner, alpha4-integrin are
blocked with specific antibodies, neural crest migration is
blocked (Lallier et al., 1994; Kil et al., 1998). These results
and others have shown that the neural crest of the trunk
primarily interacts with the extracellular matrix as the
cells migrate to their various destinations.
Another characteristic feature of neural crest cells
emerging from the hindbrain and trunk is that they
migrate in a segmented manner. Trunk neural crest cells
migrate through the rostral half of each somite but avoid
the caudal half. What molecules are responsible for
this restriction of their migratory routes? Another family
of proteins appears to be necessary for this pattern of
migration: the Ephrin receptors and ligands. These mole-
cules were first identified for their roles in repulsive guid-
ance of axonal growth (see Chapter 5). Two of the ligands,
Lerk2 and HtkL , are expressed by the caudal halves of the
somites, while the receptor, EphB3 , is expressed by the
migrating neural crest cells (Krull et al., 1997; Wang and
Anderson, 1997). If the neural crest cells are given a choice
between fibronectin or the ephrin ligand, they avoid the
ephrin. Moreover, if the soluble ligand is added to
explants of trunk, the normal migratory pattern is dis-
turbed, and the crest cells migrate on both halves of the
somite (Krull et al., 1997).
The neural crest that migrates from the cranial regions
of the neural tube has many unique features (Noden,
1975). As noted in Chapter 2, the neural tube has a con-
siderable amount of pattern in the head very early in
development. The regions of the brain are dependent on
Hox and Pax gene expression. The neural crest that
migrates from the cranial regions of the neural tube also
has positional identity, and this is also dependent on the
Hox code. The figure shows the migration of the neural
crest from the rhombomeres. The cranial crest contributes
many cells to three tissue bulges known as branchial
arches. The neural crest that migrates into these arches will
give rise to most of the skeletal and cartilage of the skull
and face. Thus, although normally we think of the neural
crest as “neural” in the head the bulk of the neural crest
cells will develop into nonneural tissues. The unique con-
tribution of the different regions of cranial neural crest has
provided an opportunity to test for the specification of
these cells and their migratory patterns. The crest cells
from rhombomeres r1 and r2 migrate into the first
(mandibular) arch, the crest from r4 into the second
(hyoid) arch, and the crest from r6 and r7 into the third
arch (Kontges and Lumsden, 1996). The crest in each of
these arches differentiates into specific skeletal elements of
the face or jaw (Figure). The neural crest from each rhom-
bomere continues to express the same pattern of Hox
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