GFRα1-deficient mice have deficits in the enteric nervous system and kidneys

Glial cell line-derived neurotrophic factor (GDNF) signals through a receptor complex composed of the Ret tyrosine kinase and a glycosylphosphatidylinositol(GPI-) anchored cell surface coreceptor, either GDNF family receptor α1 (GFRα1) or GFRα2. To investigate the usage of these coreceptors for GDNF signaling in vivo, gene targeting was used to produce mice lacking the GFRα1 coreceptor. GFRα1-deficient mice demonstrate absence of enteric neurons and agenesis of the kidney, characteristics that are reminiscent of both GDNF- and Ret-deficient mice. Midbrain dopaminergic and motor neurons in GFRα1 null mice were normal. Minimal or no neuronal losses were observed in a number of peripheral ganglia examined, including the superior cervical and nodose, which are severely affected in both Ret- and GDNF-deficient mice. These results suggest that while stringent physiologic pairing exists between GFRα1 and GDNF in renal and enteric nervous system development, significant cross-talk between GDNF and other GFRα coreceptors must occur in other neuronal populations.