The primary goal of this proposal is the generation of two powerful and innovative conditional mouse knockout strains to interrupt GDNF signaling. We propose to conditionally knock out the GDNF receptor in dopaminergic neurons using the Cre-lox recombinase system. In addition, we plan to utilize the recent technological advances in the generation of inhibitor sensitizing mutations to introduce a mutation into the RET kinase gene that will allow the specific inhibition of this arm of the GDNF signaling cascade. Overall, the study of GDNF signaling as outlined in this proposal will impact on our understanding of nigrostriatal development, Parkinson's disease pathology and the therapeutic consequences of GDNF therapy.