Schuchardt A, D'Agati V, Larsson-Blomberg L, Costantini F, Pachnis V
Department of Genetics, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
Nature. 1994 Jan 27;367(6461):380-3. doi: 10.1038/367380a0.
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.
受体酪氨酸激酶（RTKs）是一种细胞表面分子，可转导细胞生长和分化信号。c-ret原癌基因编码的RTK在大部分甲状腺乳头状癌中发生重排并持续激活，而c-ret中的种系点突变似乎是导致显性遗传癌症综合征2A型和B型多发性内分泌腺瘤病（MEN）的原因。该基因在小鼠发育中的中枢和外周神经系统（感觉、自主和肠神经节）以及排泄系统（中肾管和输尿管芽上皮）中表达，表明它可能在正常发育中发挥作用。在此我们表明，c-ret基因靶向突变的纯合小鼠可发育至足月，但出生后不久即死亡，表现为肾缺如或严重发育不全，且整个消化道缺乏肠神经元。因此，Ret是肾器官发生和肠神经发生所需信号通路的重要组成部分。
