Phosphorylation of Focal Adhesion Kinase at Y925: Role in Glia-Dependent and Independent Migration through Regulating Cofilin and N-Cadherin.

The adult neocortex is a six-layered structure, consisting of nearly continuous layers of neurons that are generated in a temporally strictly coordinated order. During development, cortical neurons originating from the ventricular zone migrate toward the Reelin-containing marginal zone in an inside-out arrangement. Focal adhesion kinase (FAK), one tyrosine kinase localizing to focal adhesions, has been shown to be phosphorylated at tyrosine 925 (Y925) by Src, an important downstream molecule of Reelin signaling. Up to date, the precise molecular mechanisms of FAK and its phosphorylation at Y925 during neuronal migration are still unclear. Combining in utero electroporation with immunohistochemistry and live imaging, we examined the function of FAK in regulating neuronal migration. We show that phosphorylated FAK is colocalized with Reelin positive Cajal-Retzius cells in the developing neocortex and hippocampus. Phosphorylation of FAK at Y925 is significantly reduced in reeler mice. Overexpression and dephosphorylation of FAK impair locomotion and translocation, resulting in migration inhibition and dislocation of both late-born and early-born neurons. These migration defects are highly correlated to the function of FAK in regulating cofilin phosphorylation and N-Cadherin expression, both are involved in Reelin signaling pathway. Thus, fine-tuned phosphorylation of focal adhesion kinase at Y925 is crucial for both glia-dependent and independent neuronal migration.