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The Journal of Neuroscience, November 19, 2003, 23(33):10633-10644
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Cellular/Molecular
Decreased Cyclin-Dependent Kinase 5 (cdk5) Activity Is Accompanied by Redistribution of cdk5 and Cytoskeletal Proteins and Increased Cytoskeletal Protein Phosphorylation in p35 Null Mice
Janice L. Hallows,1
Ken Chen,2
Ronald A. DePinho,3 and
Inez Vincent1
1The Nathan Shock Center of Excellence in the Basic Biology of Aging and Department of Pathology, University of Washington, Seattle, Washington 98195, 2Departments of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, and 3Departments of Adult Oncology, Medicine, and Genetics, Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115
Cdk5/p35 has been implicated in cytoskeletal protein phosphorylation in normal brain and in many human neurodegenerative disorders. Yet, mouse models of cdk5/p35 hyperactivity have not yielded corresponding changes in cytoskeletal protein phosphorylation. To elucidate the relationship between p35, cdk5, and the neuronal cytoskeleton, we deleted the p35 gene in mice having a pure C57BL/6 background. We found that p35 deficiency leads to a 38% reduction of cdk5 activity in adult brain. In addition, loss of p35 causes an anterograde redistribution of cdk5 toward peripheral neuronal processes. The unusual presence of nonphosphorylated neurofilament (NF) in aberrant axon fascicles and the relocation of tau and MAP2B from cell bodies and proximal neuronal processes to more distal sites of the neuropil in p35-/- mouse brain implicate p35 in neuronal trafficking, particularly in dynein-driven retrograde transport. In many axons of normal brain, cdk5 fails to colocalize with phosphorylated cytoskeletal protein epitopes. This observation, together with an unexpected increase of NF, tau, and MAP2B phosphoepitopes accompanying the decreased cdk5 activity in p35-/- mice, supports the idea that cdk5 does not phosphorylate cytoskeletal proteins directly. Rather, in structures where cdk5 does colocalize with phosphorylated cytoskeletal protein epitopes, it may function as a negative regulator of other proline-directed kinases that directly phosphorylate the proteins. Evidence for increased glycogen synthase kinase 3 (GSK3) activity in p35-/- mice suggests that GSK3 may be one such kinase regulated by cdk5. Our studies illustrate that p35 regulates the subcellular distribution of cdk5 and cytoskeletal proteins in neurons and that cdk5 has a hierarchical role in regulating the phosphorylation and function of cytoskeletal proteins.
Key words: cdk5; p35; tau phosphorylation; neurofilament phosphorylation; MAP2 phosphorylation; cytoskeletal pathology; trafficking; transport
Received June 3, 2003;
revised September 27, 2003;
accepted September 27, 2003.
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