Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons

Amy Greenstein Baynash, Kiminori Hosoda, Adel Giaid, James A Richardson, Noriak Emoto, Robert E Hammer, Masashi Yanagisawa

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Abstract

Defects in the gene encoding the endothelin-B receptor produce aganglionic megacolon and pigmentary disorders in mice and humans. We report that a targeted disruption of the mouse endothelin-3 ligand (EDN3) gene produces a similar recessive phenotype of megacolon and coat color spotting. A natural recessive mutation that results in the same developmental defects in mice, lethal spotting (ls), failed to complement the targeted EDN3 allele. The ls mice carry a point mutation of the EDN3 gene, which replaces the Arg residue at the C-terminus of the inactive intermediate big EDN3 with a Trp residue. This mutation prevents the proteolytic activation of big EDN3 by ECE-1. These findings indicate that interaction of EDN3 with the endothelin-B receptor is essential in the development of neural crest-derived cell lineages. We postulate that defects in the human EDN3 gene may cause Hirschsprung's disease.

Original languageEnglish (US)
Pages (from-to)1277-1285
Number of pages9
JournalCell
Volume79
Issue number7
DOIs
StatePublished - Dec 30 1994

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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