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.
Baynash
A G
AG
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas 75235-9050.
Hosoda
K
K
Giaid
A
A
Richardson
J A
JA
Emoto
N
N
Hammer
R E
RE
Yanagisawa
M
M
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*
D016232:Endothelins; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin