FUNCTIONAL RECEPTOR FOR GDNF ENCODED BY THE C-RET PROTOONCOGENE

GLIAL-CELL-LINE-DERIVED neurotrophic factor (GDNF) promotes the surviv al and phenotype of central dopaminergic(1,2), noradrenergic(3) and mo tor neurons(4-6), as well as various subpopulations of peripheral sens ory and sympathetic neurons(7,8). GDNF is structurally related to memb ers of the transforming growth factor (TGF)-beta superfamily(9), sever al members of which have well-characterized receptor systems(10,11); h owever, 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-re sponsive motor-neuron cell line. Ret protein could also bind GDNF and mediate survival and growth responses to GDNF upon transfection into n aive fibroblasts. Moreover, high levels of c-ret mRNA expression were found in dopaminergic neurons of the adult substantia nigra, where exo genous GDNF protected Ret-positive neurons from 6-hydroxydopamine-indu ced cell death, Thus the product of the c-ret proto-oncogene encodes a functional receptor for GDNF that may mediate its neurotrophic effect s on motor and dopaminergic neurons.