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 Pet tyrosine kinase and a glycosylphosphatidylinositol(GPl-) anchored cell surface coreceptor, either GDNF family receptor alpha 1 (GFR alpha 1) or GFR alpha 2. To investigate the usage of these coreceptors for GDNF signaling in vivo, gene targeting was used to produce mice lacking the GFR alpha 1 coreceptor. GFR alpha 1-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 GFR alpha 1 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 GFR alpha 1 and GDNF in renal and enteric nervous system development, significant cross-talk between GDNF and other GFR alpha coreceptors must occur in other neuronal populations.