Durbec P, Marcos-Gutierrez C V, Kilkenny C, Grigoriou M, Wartiowaara K, Suvanto P, Smith D, Ponder B, Costantini F, Saarma M
Division of Developmental Neurobiology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, UK.
Nature. 1996 Jun 27;381(6585):789-93. doi: 10.1038/381789a0.
Mutational analysis in humans and mice has demonstrated that the Ret, the product of the c-ret proto-oncogene, a member of the receptor tyrosine kinase (RTK) superfamily, is essential for development of the enteric nervous system and kidney. Despite the established role of Ret in mammalian embryogenesis, its cognate ligand(s) is currently unknown. Here we demonstrate, by using a Xenopus embryo bioassay, that glial-cell-line-derived neurotrophic factor (GDNF), a distant member of the transforming growth factor (TGF)-beta superfamily, signals through the Ret RTK. Furthermore, using explant cultures from wild-type and Ret-deficient mouse embryos, we show that normal c-ret function is necessary for GDNF signalling in the peripheral nervous system. Our data strongly suggest that Ret is a functional receptor for GDNF, and that GDNF, in addition to its potential role in the differentiation and survival of central nervous system neurons, has profound effects on kidney organogenesis and the development of the peripheral nervous system.
对人类和小鼠的突变分析表明，Ret作为原癌基因c-ret的产物，属于受体酪氨酸激酶（RTK）超家族成员，对肠神经系统和肾脏的发育至关重要。尽管Ret在哺乳动物胚胎发生中的作用已得到确立，但其同源配体目前仍不清楚。在这里，我们通过非洲爪蟾胚胎生物测定法证明，胶质细胞系衍生的神经营养因子（GDNF），作为转化生长因子（TGF）-β超家族的远亲成员，通过Ret RTK发出信号。此外，利用野生型和Ret缺陷型小鼠胚胎的外植体培养，我们表明正常的c-ret功能对于外周神经系统中的GDNF信号传导是必需的。我们的数据强烈表明，Ret是GDNF的功能性受体，并且GDNF除了在中枢神经系统神经元的分化和存活中可能发挥的作用外，对肾脏器官发生和外周神经系统的发育具有深远影响。
