The functional wiring of the cerebral cortex requires multiple coordinated steps of neuronal migration; the perturbation of which leads to brain malformation and various neuropsychiatric disorders such as epilepsy and schizophrenia. Rap1, a small GTPase, regulates multiple important steps of migration, including multipolar–bipolar transition and somal translocation. However, how Rap1 is differentially regulated during these phases is poorly understood. The present study demonstrates that the guanine nucleotide exchange factor, RapGEF2, but not RapGEF1 (also known as C3G), is required for multipolar–bipolar transition in a Rap1-dependent manner. In utero suppression of RapGEF2 arrested neuronal migration in the multipolar stage, ultimately resulting in subcortical band formation...[ Read more ]

The functional wiring of the cerebral cortex requires multiple coordinated steps of neuronal migration; the perturbation of which leads to brain malformation and various neuropsychiatric disorders such as epilepsy and schizophrenia. Rap1, a small GTPase, regulates multiple important steps of migration, including multipolar–bipolar transition and somal translocation. However, how Rap1 is differentially regulated during these phases is poorly understood. The present study demonstrates that the guanine nucleotide exchange factor, RapGEF2, but not RapGEF1 (also known as C3G), is required for multipolar–bipolar transition in a Rap1-dependent manner. In utero suppression of RapGEF2 arrested neuronal migration in the multipolar stage, ultimately resulting in subcortical band formation in the postnatal mouse brain. Furthermore, the GEF activity of RapGEF2 and subsequent Rap1 activation require phosphorylation by the serine/threonine kinase, cyclin-dependent kinase-5 (Cdk5). Thus, the present results demonstrate that the Cdk5-dependent activation of RapGEF2, spatial activation of Rap1 signaling, and Rap1-facilitated surface localization of N-cadherin in the intermediate zone control neuronal migration and ultimately the architecture of the mammalian cerebral cortex. Furthermore, RapGEF2 plays an intriguing role in Rap1 activation, specifically in multipolar–bipolar transition; this contrasts with the proposed role of C3G in somal translocation. These findings provide an integrated understanding of how multiple migration phases are differentially regulated by a common molecular switch.