NEURTURIN SHARES RECEPTORS AND SIGNAL-TRANSDUCTION PATHWAYS WITH GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR IN SYMPATHETIC NEURONS

Neurturin (NTN) is a neurotrophic factor that shares homology with gli al cell line-derived neurotrophic factor (GDNP), Recently, a receptor complex has been identified for GDNF that includes the Ret tyrosine ki nase receptor and a glycosylphosphatidylinositol-linked protein termed ''GDNFR alpha.'' However, differences in the phenotype of Ret and GDN F knockout animals suggest that Ret has at least one additional ligand , In this report, we demonstrate that NTN induces Ret phosphorylation in primary cultures of rat superior cervical ganglion (SCC) neurons. N TN also caused Ret phosphorylation in fibroblasts that were transferre d stably with Ret and GDNFR alpha but not in cells expressing Ret alon e. A glycosylphosphatidylinositol-linked protein also was important fo r NTN and GDNF signaling in SCG neurons; phosphatidylinositol-specific phospholipase C treatment of SCG cultures reduced the ability of NTN to phosphorylate Ret and the ability of NTN or GDNF to activate the mi togen-activated protein kinase pathway. NTN and GDNF also caused susta ined activation of Rct and the mitogen-activated protein kinase pathwa y in SCG neurons, Finally, both NTN and GDNF activated the phosphatidy linositol 3-kinase pathway in SCG neurons, which may be important for the ability of NTN and GDNF to promote neuronal survival, These data i ndicate that NTN is a physiologically relevant ligand for the Ret rece ptor and suggest that NTN may have a critical role in the development of many neuronal populations.