Several genes essential for neocortical layering have been identified in recent years, but their precise roles in this process remain to be elucidated. Mice deficient in p35—an activator of cyclin-dependent kinase 5 (Cdk5)—are characterized by a neocortex that has inverted layering. To decipher the physiological mechanisms that underlie this defect, we compared time-lapse recordings between p35-/- and wild-type cortical slices. In the p35-/- neocortex, the classic modes of radial migration—somal translocation and locomotion—were largely replaced by a distinct mode of migration: branched migration. Branched migration is cell-autonomous, associated with impaired neuronal-glial interaction and rare in neurons of scrambler mice, which are deficient in Dab1. Hence, our findings suggest that inside-out layering requires distinct functions of Reelin and p35/Cdk5 signaling, with the latter being important for proper glia-guided migration.
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