GDNF and GFRalpha: a versatile molecular complex for developing neurons.

The GDNF family ligands (GFLs) signal through the canonical signaling receptor Ret and a glycosyl-phosphatidylinositol-anchored co-receptor, GFRalpha. In recent years, signaling by GFLs has been shown to be more complex than originally assumed. The discrepant expression between GFRalphas and Ret has suggested the existence of additional signal-transducing GDNF receptors, such as NCAM. Here we summarize novel functions and Ret-independent signaling mechanisms for GDNF and GFRalpha, focusing on developing neurons. Emerging evidence indicates a prominent role of GDNF and GFRalpha in the control of neuroblast migration and chemoattraction and in the formation of neuronal synapses by a new mechanism of ligand-induced cell adhesion. Therefore, these data highlight the importance of this versatile molecular complex for nervous system development, function and regeneration.