title: Sonic hedgehog controls enteric nervous system development by patterning the extracellular matrix.
abstract: The enteric nervous system (ENS) develops from neural crest cells that migrate along the intestine, differentiate into neurons and glia, and pattern into two plexuses within the gut wall. Inductive interactions between epithelium and mesenchyme regulate gut development, but the influence of these interactions on ENS development is unknown. 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 that are known to be inhibitory to neural crest cell migration. Shh also inhibited enteric neural crest-derived cell (ENCC) proliferation, promoted neuronal differentiation, and reduced expression of Gdnf, 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.
authors.affiliation: Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA Department of Human Morphology and Developmental Biology, Faculty of Medicine, Semmelweis University, Budapest 1094, Hungary nagy.nandor@med.semmelweis-univ.hu.
authors.forename: Nandor
authors.initials: N
authors.lastname: Nagy
authors.affiliation: Department of Human Morphology and Developmental Biology, Faculty of Medicine, Semmelweis University, Budapest 1094, Hungary.
authors.forename: Csilla
authors.initials: C
authors.lastname: Barad
authors.affiliation: Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Hannah K
authors.initials: HK
authors.lastname: Graham
authors.affiliation: Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Ryo
authors.initials: R
authors.lastname: Hotta
authors.affiliation: Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Lily S
authors.initials: LS
authors.lastname: Cheng
authors.affiliation: Department of Human Morphology and Developmental Biology, Faculty of Medicine, Semmelweis University, Budapest 1094, Hungary.
authors.forename: Nora
authors.initials: N
authors.lastname: Fejszak
authors.affiliation: Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Allan M
authors.initials: AM
authors.lastname: Goldstein
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002465:Cell Movement; D002645:Chickens; D017615:Enteric Nervous System / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011784:Quail; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface
keywords: Chick; Enteric nervous system; Enteric neural crest cells; Epithelium; Extracellular matrix; Hirschsprung disease; Mouse; Patched; Ptch; Quail; Sonic hedgehog