Sonic hedgehog controls enteric nervous system development by patterning the extracellular matrix

Nandor Nagy, Csilla Barad, Hannah K. Graham, Ryo Hotta, Lily S. Cheng, Nora Fejszak, Allan M. Goldstein

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)264-275
Number of pages12
JournalDevelopment (Cambridge)
Volume143
Issue number2
DOIs
Publication statusPublished - Jan 15 2016

Keywords

  • Chick
  • Enteric nervous system
  • Enteric neural crest cells
  • Epithelium
  • Extracellular matrix
  • Hirschsprung disease
  • Mouse
  • Patched
  • Ptch
  • Quail
  • Sonic hedgehog

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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  • Cite this

    Nagy, N., Barad, C., Graham, H. K., Hotta, R., Cheng, L. S., Fejszak, N., & Goldstein, A. M. (2016). Sonic hedgehog controls enteric nervous system development by patterning the extracellular matrix. Development (Cambridge), 143(2), 264-275. https://doi.org/10.1242/dev.128132