Cyclin Dependent Kinase 5 (Cdk5)

Abstract

Neuronsmigrate from proliferative zone to their final position during brain development. Cyclin-dependent kinase 5 (Cdk5) plays an important role in neuronal migration to establish a proper structure of the brain. Analyses of Cdk5/p35-deficient mice have provided the knowledge about the role of Cdk5/p35 in neuronal migration. Over the past years, migration-related substrates of Cdk5 have been identified. Imaging analyses of neuronal migration of Cdk5/p35-deficient neurons have begun to elucidate how proper phosphorylations of these proteins by Cdk5/p35 are required for the regulation of cytoskeletal dynamics and cellular adhesion during neuronal migration. Expression of Cdk5, p35, and p39 During Brain Development Cyclin-dependent kinase 5 (Cdk5), a proline-directed serine (Ser)/threonine (Thr) kinase, had been identified as a member of the CDK family because of its close sequence homology to human CDC2 (Meyerson et al., 1992; Hellmich et al., 1992; Lew et al., 1992). Since the activity of Cdk5 is regulated by binding it with one of its neuron-specific regulatory subunits, either p35 (Lew et al., 1994; Tsai et al., 1994) or its isoform p39 (Tang et al., 1995), its activity is correlated with the level of expression of p35 and p39. Cdk5 expression is basically ubiquitous, and it is abundant in neuronal cells (Tsai et al., 1993). Expression of p35 and p39 overlaps throughout the central nervous system (CNS) during brain development, except for their expression in the cerebral cortex in the early stage, where only p35 is expressed till around E16 (Ohshima et al., 2001). High Cdk5 activity during neuronal differentiation and brain development reflects high-level expression of p35 and p39 (Tsai et al., 1993). T. Ohshima Laboratory for Molecular Brain Science, Department of Life Science and Medical Bio-Science, Science and Engineering, Waseda University, Tokyo 169-8555, Japan e-mail: ohshima@waseda.jp N.Y. Ip, L.-H. Tsai (eds.), Cyclin Dependent Kinase 5 (Cdk5), DOI: 10.1007/978-0-387-78887-6_1, Springer ScienceþBusiness Media, LLC 2008 1 Cdk5/p35 Deficiency Causes Neuronal Migration Defects in CNS Studies of the phenotypes of knockout (KO)mice have shown that Cdk5 and p35 are critical for migration of neurons to their final positions in the developing brain (Ohshima and Mikoshiba, 2002; Dhavan and Tsai, 2002). Migration defects in the cortical neurons of Cdk5 KO mice result in disruption of the laminar structures in the cerebral cortex, olfactory bulb, hippocampus, and cerebellum (Ohshima et al., 1996). p35 KO mice display a milder phenotype than Cdk5 KO mice because of the redundancy of p39 (Chae et al., 1997; Ohshima et al., 2001). p39 KO mice display no phenotype; however, p35 and p39 double KOmice display a phenotype identical to that of Cdk5 KOmice (Ko et al., 2001), confirming the redundancy of these subunits. Neuronal migration defects in Cdk5 KOmice are observed in many types of neuronal migration, but not in all types. These observations about Cdk5/p35 mutant mice indicate the occurrence of Cdk5-dependent and -independent neuronal migration. For example, radial migration of cortical neurons is Cdk5 dependent, but migration of subplate neurons seems to be Cdk5 independent in the cerebral cortex (Gilmore andHerrup, 2001). Tangentialmigration ofGABAergic neurons from ganglionic eminence to cerebral cortex is also Cdk5 independent (Gilmore and Herrup, 2001). Migration along radial glial fibers is Cdk5 dependent in many cases including radial migration of cerebral cortical neurons and inward migration of granule cells in the cerebellum (Table 1). The list of examples of Cdk5-depedent migration (Table 1) will be expanded by further analysis of mutant mice. Table 1 Comparison of migration defects in neuronal types in CNS among mutant mice Structure or neuronal type in CNS Cdk5 KO p35 KO Reeler/Dab1 mutant Olfactory bulb mitral cell þþ – –