Members of the glial cell line-derived neurotrophic factor (GDNF) family, including GDNF and Neurturin, play key roles in the control of vertebrate neuronal survivial and differentiation. GDNF is a glycosylated, disulfide-bonded homodimer that is distantly related to the TGF superfamily of growth factors. Three receptors for these factors, GFRα-1, GFRα-2, and GFRα-3 have been identified. The receptors do not contain transmembrane domains and are attached to the cell membrane by glycosyl-phosphoinositol linkage. Both GFRα-1 and GFRα-2 have been shown to mediate the GDNF-dependent and Neurturin-dependent phosphorylation and activation of the tyrosine kinase Ret. GFR-3 is expressed only during development. GFRα-2 binds Neurturin and mediates activation of RET receptor tyrosine kinase by both Neurturin and GDNF.