title: Requirement of signalling by receptor tyrosine kinase RET for the directed migration of enteric nervous system progenitor cells during mammalian embryogenesis.
abstract: The majority of neurones and glia of the enteric nervous system (ENS) are derived from the vagal neural crest. Shortly after emigration from the neural tube, ENS progenitors invade the anterior foregut and, migrating in a rostrocaudal direction, colonise in an orderly fashion the rest of the foregut, the midgut and the hindgut. We provide evidence that activation of the receptor tyrosine kinase RET by glial cell line-derived neurotrophic factor (GDNF) is required for the directional migration of ENS progenitors towards and within the gut wall. We find that neural crest-derived cells present within foetal small intestine explants migrate towards an exogenous source of GDNF in a RET-dependent fashion. Consistent with an in vivo role of GDNF in the migration of ENS progenitors, we demonstrate that Gdnf is expressed at high levels in the gut of mouse embryos in a spatially and temporally regulated manner. Thus, 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 NC cells. Twenty-four hours later and as the ENS progenitors were colonising the midgut, Gdnf expression was upregulated in a more posterior region - the caecum anlage. In further support of a role of endogenous GDNF in enteric neural crest cell migration, we find that in explant cultures GDNF produced by caecum is sufficient to attract NC cells residing in more anterior gut segments. In addition, two independently generated loss-of-function alleles of murine Ret, Ret.k- and miRet51, result in characteristic defects of neural crest cell migration within the developing gut. Finally, we identify phosphatidylinositol-3 kinase and the mitogen-activated protein kinase signalling pathways as playing crucial roles in the migratory response of enteric neural crest cells to GDNF.
authors.affiliation: Division of Molecular Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Dipa
authors.initials: D
authors.lastname: Natarajan
authors.forename: Camelia
authors.initials: C
authors.lastname: Marcos-Gutierrez
authors.forename: Vassilis
authors.initials: V
authors.lastname: Pachnis
authors.forename: Esther
authors.initials: E
authors.lastname: de Graaff
mesh_terms: D000818:Animals; D019556:COS Cells; D002432:Cecum / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D029721:Drosophila Proteins; D017615:Enteric Nervous System / Q000166:cytology* / Q000196:embryology*; D004789:Enzyme Activation; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008322:Mammals / Q000196:embryology; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009414:Nerve Growth Factors / Q000378:metabolism; D009432:Neural Crest / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D013270:Stomach / Q000166:cytology / Q000196:embryology
chemical_list: D029721:Drosophila Proteins; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse; D020928:Mitogen-Activated Protein Kinases