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The Journal of Neuroscience, July 15, 1999, 19(14):6017-6026

Migration Defects of cdk5^/ Neurons in the Developing Cerebellum is Cell Autonomous

Toshio Ohshima^{1, 2}, Edward C. Gilmore⁴, Glenn Longenecker¹, David M. Jacobowitz³, Roscoe O. Brady², Karl Herrup⁵, and Ashok B. Kulkarni¹

¹ Functional Genomics Unit, Gene Targeting Facility, National Institute of Dental and Craniofacial Research, ² Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, and ³ Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, ⁴ Department of Neuroscience and ⁵ Alzheimer Research Laboratory, Case Western Reserve Medical School, Cleveland, Ohio 44106

Cyclin-dependent kinase 5 (Cdk5) is a member of the family of cell cycle-related 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 pattern of cell migrations in cerebellum was particularly apparent, including a pronounced abnormality in the location of cerebellar Purkinje cells. Complete 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 chimeric mice by injection of cdk5^/ embryonic stem cells into host blastocysts. Analysis of the cerebellum from the resulting cdk5^/  cdk5^+/+ chimeric mice shows that the abnormal location of the mutant Purkinje cells is a cell-autonomous defect. In addition, significant numbers of granule cells remain located in the molecular layer, suggesting a failure to complete migration from the external to the internal granule cell layer. In contrast to the Purkinje and granule cell populations, all three of the deep cerebellar nuclear cell groupings form correctly and are composed of cells of both mutant and wild-type genotypes. Despite similarities of the cdk5^/ phenotype to that reported in reeler and mdab-1^/ (scrambler/yotari) mutant brains, reelin and disabled-1 mRNA were found to be normal in cdk5^/ brain. Together, the data further support the hypothesis that Cdk5 activity is required for specific components of neuronal migration that are differentially required by different neuronal cell types and by even a single neuronal cell type at different developmental stages.

Key words: neuronal migration; cdk5; cerebellar development; Purkinje cell; granule cell; cell autonomous

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19146017-10$05.00/0

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