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Functional receptor for GDNF encoded by the c-ret proto-oncogene

Abstract

GLIAL-CELL-LINE-DERIVED neurotrophic factor (GDNF) promotes the survival and phenotype of central dopaminergic1,2, noradrenergic3 and motor neurons4–6, as well as various subpopulations of peripheral sensory and sympathetic neurons7,8. GDNF is structurally related to members of the transforming growth factor (TGF)-β superfamily9, several members of which have well-characterized receptor systems10,11; 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.

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Trupp, M., Arenas, E., Fainzilber, M. et al. Functional receptor for GDNF encoded by the c-ret proto-oncogene. Nature 381, 785–789 (1996). https://doi.org/10.1038/381785a0

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