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The Journal of Neuroscience, September 1, 2001, 21(17):6758-6771
p35 and p39 Are Essential for Cyclin-Dependent Kinase 5 Function during Neurodevelopment
Jane Ko1, Sandrine Humbert3, Roderick T. Bronson4, Satoru Takahashi5, Ashok B. Kulkarni5, En Li6, and Li-Huei Tsai1, 2 1 Department of Pathology and 2 Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, 3 Curie Institute-Unité Mixte de Recherche 146 du Centre National de la Recherche Scientifique, Centre Universitaire, 91405 Orsay, France, 4 Tufts University School of Veterinary Medicine, North Grafton, Massachusetts 01536, 5 Functional Genomics Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, and 6 Cardiovascular Research Center, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129
Cyclin-dependent kinase 5 (Cdk5) plays a pivotal role in brain development and neuronal migration. Cdk5 is abundant in postmitotic, terminally differentiated neurons. The ability of Cdk5 to phosphorylate substrates is dependent on activation by its neuronal-specific activators p35 and p39. There exist striking differences in the phenotypic severity of Cdk5-deficient mice and p35-deficient mice. Cdk5-null mutants show a more severe disruption of lamination in the cerebral cortex, hippocampus, and cerebellum. In addition, Cdk5-null mice display perinatal lethality, whereas p35-null mice are viable. 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 mice show no obvious detectable abnormalities, whereas p35-/-p39-/- double-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 determine the distinct and redundant functions between p35 and p39. Our data strongly suggest that p35 and p39 are essential for Cdk5 activity during the development of the nervous system. Thus, p35 and p39 are likely to be the principal, if not the only, activators of Cdk5.
Key words: p35; p39; Cdk5; development; lamination; neuronal migration; Nudel; neurofilaments
Copyright © 2001 Society for Neuroscience 0270-6474/01/21176758-14$05.00/0
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