The GDNF/neurturin-Ret multicomponent receptor system

Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) are structurally related neurotrophic factors that play crucial roles in the survival of peripheral sensory sympathetic and dopaminergic neurons as well as motoneurons. Glial cell line-derived neurotrophic factor-deficient mice showed lack of enteric neurons and renal agenesis or dysgenesis. Surprisingly, this phenotype was strikingly similar to that of ret proto-oncogene-deficient mice, suggesting that Ret tyrosine kinase might be a functional receptor for GDNF. Recent studies demonstrated that both GDNF and NTN were able to induce Ret tyrosine phosphorylation although they did not bind to Ret with high affinity, but novel glycosylphosphatidylinositol (GPI)-linked cell-surface proteins as ligand-binding components were required for Ret activation. Since GDNF and NTN are expected as therapeutic agents in neurodegenerative disorders such as Parkinson's disease and amyotrophic lateral sclerosis, the studies on the mechanisms of their biological actions through Ret would contribute to the development of new therapeutic strategies for these diseases.