Trupp M, Arenas E, Fainzilber M, Nilsson A S, Sieber B A, Grigoriou M, Kilkenny C, Salazar-Grueso E, Pachnis V, Arumäe U
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
Nature. 1996 Jun 27;381(6585):785-9. doi: 10.1038/381785a0.
Glial-cell-line-derived neutrophic factor (GDNF) promotes the survival and phenotype of central dopaminergic noradrenergic and motor neurons, as well as various subpopulations of peripheral sensory and sympathetic neurons. GDNF is structurally related to members of the transforming growth factor (TGF)-beta superfamily, several members of which have well-characterized receptor systems; however, GDNF receptors still remain undefined. Here we show that GDNF binds to, and induces tyrosine phosphorylation of, the product of the c-ret proto-oncogene, an orphan receptor tyrosine kinase, in a GDNF-responsive motor-neuron cell line. Ret protein could also bind GDNF and mediate survival and growth responses to GDNF upon transfection into naive fibroblasts. Moreover, high levels of c-ret mRNA expression were found in dopaminergic neurons of the adult substantia nigra, where exogenous GDNF protected Ret-positive neurons from 6-hydroxydopamine-induced cell death. Thus the product of the c-ret proto-oncogene encodes a functional receptor for GDNF that may mediate its neurotrophic effects on motor and dopaminergic neurons.
胶质细胞系源性神经营养因子（GDNF）可促进中枢多巴胺能、去甲肾上腺素能和运动神经元以及外周感觉和交感神经元的各个亚群的存活和表型。GDNF在结构上与转化生长因子（TGF）-β超家族的成员相关，其中几个成员具有特征明确的受体系统；然而，GDNF受体仍未明确。在这里，我们表明GDNF在一个对GDNF有反应的运动神经元细胞系中与原癌基因c-ret的产物（一种孤儿受体酪氨酸激酶）结合并诱导其酪氨酸磷酸化。将Ret蛋白转染到未处理的成纤维细胞中后，它也能结合GDNF并介导对GDNF的存活和生长反应。此外，在成年黑质的多巴胺能神经元中发现了高水平的c-ret mRNA表达，外源性GDNF可保护Ret阳性神经元免受6-羟基多巴胺诱导的细胞死亡。因此，原癌基因c-ret的产物编码一种GDNF的功能性受体，该受体可能介导其对运动和多巴胺能神经元的神经营养作用。
