title: Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons.
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.
authors.affiliation: Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas 75235-9050.
authors.forename: A G
authors.initials: AG
authors.lastname: Baynash
authors.forename: K
authors.initials: K
authors.lastname: Hosoda
authors.forename: A
authors.initials: A
authors.lastname: Giaid
authors.forename: J A
authors.initials: JA
authors.lastname: Richardson
authors.forename: N
authors.initials: N
authors.lastname: Emoto
authors.forename: R E
authors.initials: RE
authors.lastname: Hammer
authors.forename: M
authors.initials: M
authors.lastname: Yanagisawa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016232:Endothelins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D005260:Female; D006200:Hair Color / Q000235:genetics*; D006627:Hirschsprung Disease / Q000235:genetics*; D006720:Homozygote; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D010641:Phenotype; D017354:Point Mutation; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology*
chemical_list: D016232:Endothelins; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin