N-cadherin regulates radial glial fiber-dependent migration of cortical locomoting neurons.

During cerebral cortical development, post-mitotic neurons exhibit a multi-step migration. The locomotion mode covers most of the neuronal migration path. Although for many decades, locomoting neurons have been known to migrate along radial glial fibers, how the cortical locomoting neurons attach to and migrate along radial glial fibers was largely unknown. We recently reported that N-cadherin is required for cortical neuronal migration in vivo. Knockdown or dominant negative inhibition of N-cadherin results in severe neuronal migration defects. Furthermore, suppression of Rab5-dependent endocytosis increases cell surface levels of N-cadherin and perturbs neuronal migration. We showed here that N-cadherin overexpression, which would mimic Rab5 suppression, weakly suppressed neuronal migration, suggesting that excess N-cadherin also disturbs neuronal migration. Interestingly, however, N-cadherin knockdown and overexpression in neurons resulted in different morphologies. While N-cadherin-overexpressing cells closely attached to the radial glial fibers similar to control or Rab5-knockdown cells, N-cadherin knockdown weakened the attachment as the average distance between the soma and radial glial fibers was significantly increased. Taken together, these findings suggest that N-cadherin controls the neuronal attachment to radial glial fibers and that N-cadherin-mediated adhesion complexes are reconstituted through Rab GTPases-dependent endocytic pathways to maintain the proper surface N-cadherin level and to promote neuronal migration.