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.
Schuchardt
A
A
Department of Genetics, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
D'Agati
V
V
Larsson-Blomberg
L
L
Costantini
F
F
Pachnis
V
V
D000818:Animals; D002678:Chimera; D029721:Drosophila Proteins; D017615:Enteric Nervous System / Q000002:abnormalities* / Q000196:embryology; D005260:Female; D018095:Germ-Line Mutation; D006579:Heterozygote; D006720:Homozygote; D007422:Intestines / Q000196:embryology / Q000294:innervation; D007668:Kidney / Q000002:abnormalities* / Q000196:embryology; D008297:Male; D051379:Mice; D009154:Mutation; D009432:Neural Crest / Q000166:cytology; D009474:Neurons / Q000166:cytology*; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology; D051096:Proto-Oncogene Proteins c-ret; D011519:Proto-Oncogenes; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction
D029721:Drosophila Proteins; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse