Functional receptor for GDNF encoded by the c-ret proto-oncogene.
Trupp, Miles; Arenas, Ernest; Fainzilber, Michael; Nilsson, Ann-Sofie; Sieber, Beth-Anne; Grigoriou, Maria; Kilkenny, Carol; Salazar-Grueso, Edgar; Pachnis, Vassilis; Arumae, Urmas; Sariola, Hannu; Saarma, Mart; Ibanez, Carlos F.
[Letter] Nature. 381(6585):785-789, June 27, 1996.

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GLIAL-CELL-LINE-DERIVED neurotrophic factor (GDNF) promotes the survival and phenotype of central dopaminergic [1,2], noradrenergic [3] and motor neurons [4-6], as well as various subpopulations of peripheral sensory and sympathetic neurons [7,8]. GDNF is structurally related to members of the transforming growth factor (TGF)-beta superfamily [9], several members of which have well-characterized receptor systems [10,11]; 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 Retpositive 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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