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

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.

Pubmed ID: 8001160


  • Baynash AG
  • Hosoda K
  • Giaid A
  • Richardson JA
  • Emoto N
  • Hammer RE
  • Yanagisawa M



Publication Data

December 30, 1994

Associated Grants


Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Endothelins
  • Female
  • Hair Color
  • Hirschsprung Disease
  • Homozygote
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Molecular Sequence Data
  • Phenotype
  • Point Mutation
  • Receptor, Endothelin B
  • Receptors, Endothelin