Migration defects of cdk5(-/-) neurons in the developing cerebellum is cell autonomous

Cyclin-dependent kinase 5 (Cdk5) is a member of the family of cell cycle-re lated kinases. Previous neuropathological analysis of cdk5(-/-) mice showed significant changes in CNS development in regions from cerebral cortex to brainstem. Among the defects in these animals, a disruption of the normal p attern of cell migrations in cerebellum was particularly apparent, includin g a pronounced abnormality in the location of cerebellar Purkinje cells. Co mplete analysis of this brain region is hampered in the mutant because most of cerebellar morphogenesis occurs after birth and the cdk5(-/-) mice die in the perinatal period. To overcome this disadvantage, we have generated c himeric mice by injection of cdk5(-/-) embryonic stem cells into host blast ocysts. Analysis of the cerebellum from the resulting cdk5(-/-) <-> cdk5(+/ +) chimeric mice shows that the abnormal location of the mutant Purkinje ce lls is a cell-autonomous defect. In addition, significant numbers of granul e cells remain located in the molecular layer, suggesting a failure to comp lete migration from the external to the internal granule cell layer. In con trast to the Purkinje and granule cell populations, all three of the deep c erebellar nuclear cell groupings form correctly and are composed of cells o f both mutant and wild-type genotypes. Despite similarities of the cdk5(-/- ) phenotype to that reported in reeler and mdab-1(-/-) (scrambler/yotari) m utant brains, reelin and disabled-1 mRNA were found to be normal in cdk5(-/ -) brain. Together, the data further support the hypothesis that Cdk5 activ ity is required for specific components of neuronal migration that are diff erentially required by different neuronal cell types and by even a single n euronal cell type at different developmental stages.