Cadherin-6 controls neuronal migration during mouse neocortical development via an integrin-mediated pathway.

During neocortical development, neuronal migration is highly regulated by multiple signaling cascades, including the cell adhesion molecules. Cadherin-6 (CDH6), an unusual cadherin molecule containing an RGD integrin-binding motif, has multiple functions in the developing nervous system, but whether it contributes to neuronal migration and positioning during neocortical development remains unknown. Here, we investigated the role of CDH6 in the developing cerebral cortex. Cdh6 knockdown (KD) using in utero electroporation revealed that CDH6 inhibition caused impaired radial migration and abnormal positioning of neurons. Time-lapse imaging analysis revealed that CDH6 is important for proper neuronal motility. Mechanistically, we show that CDH6 promotes the activation of integrin β1 on migrating neurons. The defect in neuronal migration caused by Cdh6 KD was rescued by moderate overexpression of integrin β1 and a KD-resistant form of wild-type CDH6, but not by CDH6 with a mutated RGD motif. These results suggest that CDH6 is required for cortical excitatory neurons to migrate radially by controlling integrin-mediated cell motility.