Netrins and DCC in the guidance of migrating neural crest-derived cells in the developing bowel and pancreas.
Vagal neural crest-derived precursors of the enteric nervous system colonize the bowel by descending within the enteric mesenchyme. Perpendicular secondary migration, toward the mucosa and into the pancreas, result, respectively, in the formation of submucosal and pancreatic ganglia. We tested the hypothesis that netrins guide these secondary migrations. Studies using RT-PCR, in situ hybridization, and immunocytochemistry indicated that netrins (netrins-1 and -3 mice and netrin-2 in chicks) and netrin receptors [deleted in colorectal cancer (DCC), neogenin, and the adenosine A2b receptor] are expressed by the fetal mucosal epithelium and pancreas. Crest-derived cells expressed DCC, which was developmentally regulated. Crest-derived cells migrated out of explants of gut toward cocultured cells expressing netrin-1 or toward cocultured explants of pancreas. Crest-derived cells also migrated inwardly toward the mucosa of cultured rings of bowel. These migrations were specifically blocked by antibodies to DCC and by inhibition of protein kinase A, which interferes with DCC signaling. Submucosal and pancreatic ganglia were absent at E12.5, E15, and P0 in transgenic mice lacking DCC. Netrins also promoted the survival/development of enteric crest-derived cells. The formation of submucosal and pancreatic ganglia thus involves the attraction of DCC-expressing crest-derived cells by netrins.
Jiang
Yan
Y
Department of Anatomy and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Liu
Min-tsai
MT
Gershon
Michael D
MD
D000818:Animals; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement; D002642:Chick Embryo; D000075389:DCC Receptor; D004247:DNA / Q000235:genetics; D017615:Enteric Nervous System / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D005724:Ganglia / Q000002:abnormalities / Q000196:embryology; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D000075388:Netrin-1; D000075385:Netrins; D009432:Neural Crest / Q000166:cytology* / Q000196:embryology / Q000378:metabolism*; D010179:Pancreas / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D011956:Receptors, Cell Surface; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D015815:Cell Adhesion Molecules; D000075389:DCC Receptor; C501909:DCC protein, human; C501910:Dcc protein, mouse; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D000075385:Netrins; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C119569:netrin-3; D000075388:Netrin-1; C088894:netrin-2; D004247:DNA