MICE LACKING P35, A NEURONAL SPECIFIC ACTIVATOR OF CDK5, DISPLAY CORTICAL LAMINATION DEFECTS, SEIZURES, AND ADULT LETHALITY

The adult mammalian cortex is characterized by a distinct laminar stru cture generated through a well-defined pattern of neuronal migration. Successively generated neurons are layered in an ''inside-out'' manner to produce six cortical laminae. We demonstrate here that p35, the ne uronal-specific activator of cyclin-dependent kinase 5, plays a key ro le in proper neuronal migration. Mice lacking p35, and thus p35/cdk5 k inase activity, display severe cortical lamination defects and suffer from sporadic adult lethality and seizures. Histological examination r eveals that the mutant mice lack the characteristic laminated structur e of the cortex. Neuronal birth-dating experiments indicate a reversed packing order of cortical neurons such that earlier born neurons resi de in superficial layers and later generated neurons occupy deep layer s. The phenotype of p35 mutant mice thus demonstrates that the formati on of cortical laminar structure depends on the action of the p35/cdk5 kinase.