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Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice.

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genetics, Base Sequence, Chromosome Mapping, Gene Deletion, Hair Color, Hirschsprung Disease, embryology, Homozygote, Animals, Mice, Mice, Knockout, Mice, Mutant Strains, Molecular Sequence Data, Mutation, Neural Crest, growth & development, Phenotype, Receptor, Endothelin B, Receptors, Endothelin

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      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.

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      Most cited references 29

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      A novel potent vasoconstrictor peptide produced by vascular endothelial cells.

      An endothelium-derived 21-residue vasoconstrictor peptide, endothelin, has been isolated, and shown to be one of the most potent vasoconstrictors known. Cloning and sequencing of preproendothelin complementary DNA shows that mature endothelin is generated through an unusual proteolytic processing, and regional homologies to a group of neurotoxins suggest that endothelin is an endogenous modulator of voltage-dependent ion channels. Expression of the endothelin gene is regulated by several vasoactive agents, indicating the existence of a novel cardiovascular control system.
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        Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery.

        We employed homologous recombination in embryonic stem cells to produce mice lacking functional LDL receptor genes. Homozygous male and female mice lacking LDL receptors (LDLR-/- mice) were viable and fertile. Total plasma cholesterol levels were twofold higher than those of wild-type litter-mates, owing to a seven- to ninefold increase in intermediate density lipoproteins (IDL) and LDL without a significant change in HDL. Plasma triglyceride levels were normal. The half-lives for intravenously administered 125I-VLDL and 125I-LDL were prolonged by 30-fold and 2.5-fold, respectively, but the clearance of 125I-HDL was normal in the LDLR-/- mice. Unlike wild-type mice, LDLR-/- mice responded to moderate amounts of dietary cholesterol (0.2% cholesterol/10% coconut oil) with a major increase in the cholesterol content of IDL and LDL particles. The elevated IDL/LDL level of LDLR-/- mice was reduced to normal 4 d after the intravenous injection of a recombinant replication-defective adenovirus encoding the human LDL receptor driven by the cytomegalovirus promoter. The virus restored expression of LDL receptor protein in the liver and increased the clearance of 125I-VLDL. We conclude that the LDL receptor is responsible in part for the low levels of VLDL, IDL, and LDL in wild-type mice and that adenovirus-encoded LDL receptors can acutely reverse the hypercholesterolemic effects of LDL receptor deficiency.
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          Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret.

          Receptor tyrosine kinases (RTKs) are cell-surface molecules that transduce signals for cell growth and differentiation. The RTK encoded by the c-ret proto-oncogene is rearranged and constitutively activated in a large proportion of thyroid papillary carcinomas, and germ-line point mutations in c-ret seem to be responsible for the dominantly inherited cancer syndromes multiple endocrine neoplasia (MEN) types 2A and B. The gene is expressed in the developing central and peripheral nervous systems (sensory, autonomic and enteric ganglia) and the excretory system (Wolffian duct and ureteric bud epithelium) of mice, indicating that it may play a role in normal development. Here we show that mice homozygous for a targeted mutation in c-ret develop to term, but die soon after birth, showing renal agenesis or severe dysgenesis, and lacking enteric neurons throughout the digestive tract. Ret is thus an essential component of a signalling pathway required for renal organogenesis and enteric neurogenesis.
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            Journal
            8001159

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