NEURTURIN RESPONSIVENESS REQUIRES A GPI-LINKED RECEPTOR AND THE RET RECEPTOR TYROSINE KINASE

Neurturin (NTN)(1) is a recently identified homologue of glial-celllin e-derived neurotrophic factor (GDNF)(2). Both factors promote the surv ival of a variety of neurons(1-5), and GDNF is required for the develo pment of the enteric nervous system and kidney(6-8). GDNF signals thro ugh a receptor complex consisting of the receptor tyrosine kinase Ret and a glycosyl-phosphatidylinositol (GPI)-linked receptor termed GDNFR -alpha(9-13). Here we report the cloning of a new GPI-linked receptor termed NTNR-alpha that is homologous with GDNFR-alpha and is widely ex pressed in the nervous system and other tissues. By using microinjecti on to introduce expression plasmids into neurons, we show that coexpre ssion of NTNR-alpha with Ret confers a survival response to neurturin but not GDNF, and that coexpression of GDNFR-alpha with Ret confers a survival response to GDNF but not neurturin. Our findings indicate tha t GDNF and neurturin promote neuronal survival by signalling through s imilar multicomponent receptors that consist of a common receptor tyro sine kinase and a member of a GPI-linked family of receptors that dete rmines ligand specificity.