Neurturin responsiveness requires a GPI-linked receptor and the Ret receptor tyrosine kinase

Neurturin (NTN)1 is a recently identified homologue of glial-cell-line-derived neurotrophic factor (GDNF)2. Both factors promote the survival of a variety of neurons1,2,3,4,5, and GDNF is required for the development of the enteric nervous system and kidney6,7,8. GDNF signals through a receptor complex consisting of the receptor tyrosine kinase Ret and a glycosyl-phosphatidylinositol (GPI)-linked receptor termed GDNFR-α9,10,11,12,13. Here we report the cloning of a new GPI-linked receptor termed NTNR-α that is homologous with GDNFR-α and is widely expressed in the nervous system and other tissues. By using microinjection to introduce expression plasmids into neurons, we show that coexpression of NTNR-α with Ret confers a survival response to neurturin but not GDNF, and that coexpression of GDNFR-α with Ret confers a survival response to GDNF but not neurturin. Our findings indicate that GDNF and neurturin promote neuronal survival by signalling through similar multicomponent receptors that consist of a common receptor tyrosine kinase and a member of a GPI-linked family of receptors that determines ligand specificity.