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-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(-/-) left arrow over right arrow 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.
Functional Genomics Unit, Gene Targeting Facility, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
T
T
Ohshima
E C
EC
Gilmore
G
G
Longenecker
D M
DM
Jacobowitz
R O
RO
Brady
K
K
Herrup
A B
AB
Kulkarni
D000375:Aging / Q000502:physiology; D000818:Animals; D001755:Blastocyst; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D002531:Cerebellum / Q000002:abnormalities* / Q000254:growth & development / Q000473:pathology; D002678:Chimera; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000235:genetics; D011689:Purkinje Cells / Q000473:pathology / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D000091042:Reelin Protein; D012697:Serine Endopeptidases; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D014158:Transcription, Genetic
D015816:Cell Adhesion Molecules, Neuronal; C103773:Dab1 protein, mouse; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D000091042:Reelin Protein; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases