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further tyrosine kinase receptors and their ligands have been described by
others to affect the development and, in particular, the migration of neural
crest cells. c-Ret encodes a tyrosine kinase receptor that recognizes glial cell
line-derived neurotrophic factor (GDNF) as a ligand. Mutations in c-Ret
cause Hirschsprung disease, characterized by the absence of a portion of the
enteric nervous system (for review see Taraviras and Pachnis, 1999). The
majority of neurons and glia of the enteric nervous system are derived from
the vagal neural crest. Shortly after emigration from the neural tube, these
neural crest cells invade the anterior foregut and migrate in a rostro-caudal
direction to colonize the remainder of the gut. c-Ret is expressed in the vagal
neural crest and in their derivatives, the neurons of the enteric nervous system.
Activation of the receptor tyrosine kinase c-Ret is required for development of
the enteric nervous system (Schuchardt et al., 1994). Several mechanisms were
suggested to account for the observed absence of the enteric nervous system in
c-Ret mutant mice. Since apoptotic cell death is enhanced in the foregut of
embryos lacking c-Ret, it was originally suggested that c-Ret is required for
survival of enteric neural crest cells and their derivatives (Taraviras et al.,
1999). However, a recent report demonstrates that also an impaired migration
might contribute to the impaired development of the enteric nervous system
(Natarajan et al., 2002). Neural crest cells in explants of embryonic intestine
migrate towards an exogenous source of GDNF in a c-Ret-dependent fashion.
In addition, the rate of migration of neural crest cells in c-Ret mutant mice
appears to be impaired. Consistent with a role of GDNF in the migration of
enteric nervous system progenitors, GDNF is expressed at high levels in the
gut of mouse embryos in a spatially and temporally regulated manner. During
invasion of the foregut by vagal-derived neural crest cells, expression of
GDNF was restricted to the mesenchyme of the stomach, ahead of the
invading neural crest cells. Twenty-four hours later, when neural crest cells
colonize the midgut, GDNF expression was upregulated in a more posterior
region of the gut. Thus, c-Ret might be required for migration and survival of
neural crest cells in the developing gut.
Eph tyrosine kinase receptors and their ligands recognize and provide
repulsive cues during axonal pathfinding. Eph-mediated directional cues do
not only guide axons, but also neural crest cells. Neural crest cells migrate in a
segmental manner, for instance in the trunk when they pass on the ventral
pathway through the rostral but not caudal somite. The addition of soluble
ephrin-B1 to the developing chick embryo results in a loss of the metameric
migratory pattern and in a disorganization of neural crest cell movement. In
mice, the mutation of EphB2 results in an abnormal migration pattern of
cranial neural crest. Thus, Eph receptor tyrosine kinases and their ligands can
guide neural crest cells during their migration and mediate inhibitory activities
necessary to constrain the migration to specific territories (reviewed by
Drescher, 1997; Wilkinson, 2001).
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