Abstract
During cerebral cortex development, pyramidal neurons migrate through the intermediate zone and integrate into the cortical plate. These neurons undergo the multipolar–bipolar transition to initiate radial migration. While perturbation of this polarity acquisition leads to cortical malformations, how this process is initiated and regulated is largely unknown. Here we report that the specific upregulation of the Rap1 guanine nucleotide exchange factor, RapGEF2, in migrating neurons corresponds to the timing of this polarity transition. In utero electroporation and live-imaging studies reveal that RapGEF2 acts on the multipolar–bipolar transition during neuronal migration via a Rap1/N-cadherin pathway. Importantly, activation of RapGEF2 is controlled via phosphorylation by a serine/threonine kinase Cdk5, whose activity is largely restricted to the radial migration zone. Thus, the specific expression and Cdk5-dependent phosphorylation of RapGEF2 during multipolar–bipolar transition within the intermediate zone are essential for proper neuronal migration and wiring of the cerebral cortex.
Highlights
During cerebral cortex development, pyramidal neurons migrate through the intermediate zone and integrate into the cortical plate
In utero electroporation and live-imaging studies reveal that the specific activation of Rap1/N-cadherin pathway by RapGEF2 in the intermediate zone is required for multipolar–bipolar transition during neuronal migration
To detect the spatial expression pattern of RapGEF2 in the cortical wall of developing mouse brains, we examined coronal cortical sections from mouse embryos collected at E12, E15 and E17
Summary
Pyramidal neurons migrate through the intermediate zone and integrate into the cortical plate These neurons undergo the multipolar–bipolar transition to initiate radial migration. The specific expression and Cdk5-dependent phosphorylation of RapGEF2 during multipolar–bipolar transition within the intermediate zone are essential for proper neuronal migration and wiring of the cerebral cortex. Activation of Rap[1] depends on its specific guanine nucleotide exchange factors (GEFs) and RapGEF1 ( known as C3G) is reported to control somal translocation triggered by Reelin[17,18,19]. In utero electroporation and live-imaging studies reveal that the specific activation of Rap1/N-cadherin pathway by RapGEF2 in the intermediate zone is required for multipolar–bipolar transition during neuronal migration. The precise control of RapGEF2 activity through its specific expression and Cdk5-dependent phosphorylation is critical for proper neuronal and cortical circuit assembly
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