TY - JOUR
T1 - Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice
AU - Hosoda, Kiminori
AU - Hammer, Robert E
AU - Richardson, James A
AU - Baynash, Amy Greenstein
AU - Cheung, Jason C.
AU - Giaid, Adel
AU - Yanagisawa, Masashi
N1 - Funding Information:
Correspondence should be addressed to M. Y. We thank Joachim Herz for the mouse ES cell line and for helpful comments, Shun lshibashi for technical suggestions, Lucy Lindquist, Jeff Cormier, Gita Singh, and Damiane deWit for technical assistance, Alan Bradley for LIF-producing ST0 cells, Aravinda Chakravarti and Raj Kapur for discussions, and Mike Brown and Joe Goldstein for criticizing this manuscript. M. Y. and K. H. are an Associate Investigator and an Associate of the Howard Hughes Medical Institute, respectively. This study is supported in part by research grants from the Perot Family Foundation and the W. M. Keck Foundation (M. Y. and R. E. H.) and the Medical Research Council of Canada and the Heart and Stroke Association of Canada (A. G.).
PY - 1994/12/30
Y1 - 1994/12/30
N2 - 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.
AB - 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.
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U2 - 10.1016/0092-8674(94)90017-5
DO - 10.1016/0092-8674(94)90017-5
M3 - Article
C2 - 8001159
AN - SCOPUS:0028639196
SN - 0092-8674
VL - 79
SP - 1267
EP - 1276
JO - Cell
JF - Cell
IS - 7
ER -