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 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.