p35 and p39 are essential for cyclin-dependent kinase 5 function during neurodevelopment

Cyclin-dependent kinase 5 (Cdk5) plays a pivotal role in brain development and neuronal migration. Cdk5 is abundant in postmitotic, terminally differe ntiated neurons. The ability of Cdk5 to phosphorylate substrates is depende nt on activation by its neuronal-specific activators p35 and p39. There exi st striking differences in the phenotypic severity of Cdk5-deficient mice a nd p35-deficient mice. Cdk5-null mutants show a more severe disruption of l amination in the cerebral cortex, hippocampus, and cerebellum. In addition, Cdk5-null mice display perinatal lethality, whereas p35-null mice are viab le. These discrepancies have been attributed to the function of other Cdk5 activators, such as p39. To understand the roles of p39 and p35, we created p39-null mice and p35/p39 compound-mutant mice. Interestingly, p39-null mi ce show no obvious detectable abnormalities, whereas p35(-/-)p39(-/-) doubl e-null mutants are perinatal lethal. We show here that the p35(-/-)p39(-/-) mutants exhibit phenotypes identical to those of the Cdk5-null mutant mice . Other compound-mutant mice with intermediate phenotypes allow us to deter mine the distinct and redundant functions between p35 and p39. Our data str ongly suggest that p35 and p39 are essential for Cdk5 activity during the d evelopment of the nervous system. Thus, p35 and p39 are likely to be the pr incipal, if not the only, activators of Cdk5.