Csk-dependent and -independent control of Src family kinases directs neuronal migration in the developing cerebral cortex

Fyn, a proto-oncogene product of Src family kinases (SFKs), plays pivotal roles in various pathological and physiological events, including cancer and immunity. C-terminal Src kinase (Csk) is a negative regulator for all SFKs, including Fyn, and acts as a tumor suppressor, but its involvement in normal tissue morphogenesis remains unclear. Here, we show that Csk plays essential roles in cerebral cortical development. In vivo knockdown of Csk, as well as constitutive active form of Fyn (CA-Fyn), disturbs neuronal migration and immature neurite formation without affecting neural progenitor proliferation and neuronal differentiation in the developing cerebral cortex. Although overactivation of SFKs is known to downregulate cadherin-mediated cell-to-cell adhesion, both Csk knockdown and CA-Fyn promote attachments between immature neurons. Interestingly, CA-Fyn, but not Csk knockdown, increases N-cadherin cell surface levels. Csk knockdown upregulates SFK activities near the plasma membrane, but not in total cell lysates, whereas CA-Fyn promotes both, implying a Csk-independent role of cytosolic Fyn in N-cadherin plasma membrane localization. In contrast, Csk knockdown and CA-Fyn commonly promote cell surface levels of L1-CAM, an immunoglobulin superfamily cell adhesion molecule that controls cortical neuronal migration. Thus, Csk-mediated local regulation of membrane-bound SFK activities appears essential for cortical neuronal migration through fine-tuning of intercellular attachment strength between immature neurons.