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Epithelial-mesenchymal recombinations were constructed using avian hindgut mesenchyme and non-intestinal epithelium from the bursa of Fabricius. These recombinations led to abnormally large and ectopically positioned ganglia. We hypothesized that Sonic hedgehog (Shh), a secreted intestinal epithelial protein not expressed in the bursa, mediates this effect. Inhibition of Shh signaling, by addition of cyclopamine or a function-blocking antibody, resulted in large, ectopic ganglia adjacent to the epithelium. Shh overexpression, achieved in ovo using Shh-encoding retrovirus and in organ culture using recombinant protein, led to intestinal aganglionosis. Shh strongly induced the expression of versican and collagen type IX, whereas cyclopamine reduced expression of these chondroitin sulfate proteoglycans known to be inhibitory to neural crest cell migration. Shh also inhibited ENCC proliferation, promoted neuronal differentiation, and reduced expression of glial-derived neurotrophic factor, a key regulator of ENS formation. Ptc1 and Ptc2 were not expressed by ENCCs, and migration of isolated ENCCs was not inhibited by Shh protein. These results suggest that epithelial-derived Shh acts indirectly on the developing ENS by regulating the composition of the intestinal microenvironment.<\/jats:p>","DOI":"10.1242\/dev.128132","type":"journal-article","created":{"date-parts":[[2015,12,16]],"date-time":"2015-12-16T21:51:38Z","timestamp":1450302698000},"source":"Crossref","is-referenced-by-count":40,"title":["Sonic hedgehog controls enteric nervous system development by patterning the extracellular matrix"],"prefix":"10.1242","author":[{"given":"Nandor","family":"Nagy","sequence":"first","affiliation":[{"name":"Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA"},{"name":"Department of Human Morphology and Developmental Biology, Faculty of Medicine, Semmelweis University, Budapest-1094, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Csilla","family":"Barad","sequence":"additional","affiliation":[{"name":"Department of Human Morphology and Developmental Biology, Faculty of Medicine, Semmelweis University, Budapest-1094, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Graham","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Hotta","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lily","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora","family":"Fejszak","sequence":"additional","affiliation":[{"name":"Department of Human Morphology and Developmental Biology, Faculty of Medicine, Semmelweis University, Budapest-1094, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan M.","family":"Goldstein","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042608293102400_DEV128132C1","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/S0091-679X(08)00209-4","article-title":"In situ hybridization analysis of chick embryos in whole-mount and tissue sections","volume":"87","author":"Acloque","year":"2008","journal-title":"Methods Cell Biol."},{"key":"2021042608293102400_DEV128132C2","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1016\/j.ydbio.2013.08.006","article-title":"Enteric neural crest-derived cells promote their migration by modifying their microenvironment through tenascin-C production","volume":"382","author":"Akbareian","year":"2013","journal-title":"Dev. 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