title: Enteric neurons synthesize netrins and are essential for the development of the vagal sensory innervation of the fetal gut.
abstract: During fetal life, vagal sensory fibers establish a reproducible distribution in the gut that includes an association with myenteric ganglia. Previous work has shown that netrin is expressed in the bowel wall and, by acting on its receptor, deleted in colorectal cancer (DCC), mediates the guidance of vagal sensory axons to the developing gut. Because the highest concentration of netrins in fetal bowel is in the endoderm, we tested the hypothesis that the ingrowth of vagal afferents to the gut would be independent of the presence of enteric neurons, although enteric neurons might influence the internal distribution of these fibers. Surprisingly, experiments indicated that the vagal sensory innervation is intrinsic neuron-dependent. To examine the vagal innervation in the absence of enteric ganglia, fetal Ret -/- mice were labeled by applying DiI bilaterally to nodose ganglia. In Ret -/- mice, DiI-labeled vagal sensory axons descended in paraesophageal trunks as far as the proximal stomach, which contains neurons, but did not enter the aganglionic bowel. To determine whether neurons produce netrins, enteric neural-crest-derived cells (ENCDCs) were immunoselected from E15 rat gut. Transcripts encoding netrin-1 and -3 were not detected in the ENCDCs, but appeared after they had given rise to neurons. When these neurons were cocultured with cells expressing c-Myc-tagged netrin-1, the neurons displayed netrin-1, but not c-Myc, immunoreactivity. Enteric neurons thus synthesize netrins. The extent to which neuronal netrin accounts for the dependence of the vagal sensory innervation on intrinsic neurons, remains to be determined.
authors.affiliation: Department of Pediatrics, Division of Gastroenterology and Nutrition, McMaster University, Hamilton, Ontario. ratcli@mcmaster.ca
authors.forename: Elyanne M
authors.initials: EM
authors.lastname: Ratcliffe
authors.forename: Lena
authors.initials: L
authors.lastname: Fan
authors.forename: Tandi J
authors.initials: TJ
authors.lastname: Mohammed
authors.forename: Monique
authors.initials: M
authors.lastname: Anderson
authors.forename: Alcmène
authors.initials: A
authors.lastname: Chalazonitis
authors.forename: Michael D
authors.initials: MD
authors.lastname: Gershon
mesh_terms: D000818:Animals; D015153:Blotting, Western; D017615:Enteric Nervous System / Q000166:cytology / Q000196:embryology / Q000502:physiology*; D041981:Gastrointestinal Tract / Q000196:embryology / Q000294:innervation* / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000096:biosynthesis*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D000075388:Netrin-1; D000075385:Netrins; D055495:Neurogenesis / Q000502:physiology*; D051096:Proto-Oncogene Proteins c-ret / Q000172:deficiency / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D011984:Sensory Receptor Cells / Q000166:cytology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis*; D014630:Vagus Nerve / Q000166:cytology / Q000378:metabolism*
chemical_list: D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D000075385:Netrins; C000617353:Ntn1 protein, mouse; C000617354:Ntn1 protein, rat; D025521:Tumor Suppressor Proteins; C119569:netrin-3; D000075388:Netrin-1; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse