Hosoda K, Hammer RE, Richardson JA, Baynash AG, Cheung JC, Giaid A, Yanagisawa M:
Targeted and natural (piebald-lethal) mutations of endothelin-B
receptor gene produce megacolon associated with spotted coat color
in mice.
Cell 1994 Dec 30;79(7):1267-76
ABSTRACT
Endothelins act on two subtypes of G protein-coupled receptors,
termed endothelin-A and endothelin-B receptors. We report a targeted
disruption of the mouse endothelin-B receptor (EDNRB) gene that
results in aganglionic megacolon associated with coat color
spotting, resembling a hereditary syndrome of mice, humans, and
other mammalian species. Piebald-lethal (sl) mice exhibit a
recessive phenotype identical to that of the EDNRB knockout mice. In
crossbreeding studies, the two mutations show no complementation.
Southern blotting revealed a deletion encompassing the entire EDNRB
gene in the sl chromosome. A milder allele, piebald (s), which
produces coat color spotting only, expresses low levels of
structurally intact EDNRB mRNA and protein. These findings indicate
an essential role for EDNRB in the development of two neural
crest-derived cell lineages, myenteric ganglion neurons and
epidermal melanocytes. We postulate that defects in the human EDNRB
gene cause a hereditary form of Hirschsprung's disease that has
recently been mapped to human chromosome 13, in which EDNRB is
located.
