GFR-ALPHA-1-DEFICIENT MICE HAVE DEFICITS IN THE ENTERIC NERVOUS-SYSTEM AND KIDNEYS

Glial cell line-derived neurotrophic factor (GDNF) signals through a r eceptor complex composed of the Pet tyrosine kinase and a glycosylphos phatidylinositol(GPl-) anchored cell surface coreceptor, either GDNF f amily receptor alpha 1 (GFR alpha 1) or GFR alpha 2. To investigate th e usage of these coreceptors for GDNF signaling in vivo, gene targetin g was used to produce mice lacking the GFR alpha 1 coreceptor. GFR alp ha 1-deficient mice demonstrate absence of enteric neurons and agenesi s of the kidney, characteristics that are reminiscent of both GDNF- an d Ret-deficient mice. Midbrain dopaminergic and motor neurons in GFR a lpha 1 null mice were normal. Minimal or no neuronal losses were obser ved in a number of peripheral ganglia examined, including the superior cervical and nodose, which are severely affected in both Ret- and GDN F-deficient mice. These results suggest that while stringent physiolog ic pairing exists between GFR alpha 1 and GDNF in renal and enteric ne rvous system development, significant cross-talk between GDNF and othe r GFR alpha coreceptors must occur in other neuronal populations.