GFRα1 Regulates Purkinje Cell Migration by Counteracting NCAM Function

During embryonic development of the cerebellum, Purkinje cells (PCs) migrate away from the ventricular zone to form the PC plate. The mechanisms that regulate PC migration are incompletely understood. Here, we report that the neurotrophic receptor GFR alpha 1 is transiently expressed in developing PCs and loss of GFR alpha 1 delays PC migration. Neither GDNF nor RET, the canonical GFR alpha 1 ligand and co-receptor, respectively, contribute to this process. Instead, we found that the neural cell adhesion molecule NCAM is co-expressed and directly interacts with GFR alpha 1 in embryonic PCs. Genetic reduction of NCAM expression enhances wild-type PC migration and restores migration in GFR alpha 1 mutants, indicating that NCAM restricts PC migration in the embryonic cerebellum. In vitro experiments indicated that GFR alpha 1 can function both in cis and trans to counteract NCAM and promote PC migration. Collectively, our studies show that GFR alpha 1 contributes to PC migration by limiting NCAM function.