Noting the emerging role for cyclin-dependent kinase 5 (Cdk5) in the developing and mature brain, Kim et al. searched rat striatal extracts for proteins that interacted with Cdk5 together with its neuron-specific regulatory subunit, P35 (P35/Cdk5). They identified two proteins known to exist in a complex with WAVE1 [Wiskott-Aldrich syndrome protein (WASP)-family verprolin homologous protein 1], a protein implicated in the regulation of actin dynamics. WAVE1 itself was also present in the complex of P35/Cdk5-binding proteins and interacted directly with P35. Cdk5 phosphorylated WAVE1 in vitro, and treatment of mouse striatal slices with a Cdk5 inhibitor led to reduced WAVE1 phosphorylation; moreover, primary cultures of cortical neurons from mice lacking Cdk5 showed reduced WAVE1 phosphorylation compared with wild-type neurons. Preincubation with p35/Cdk5 and MgATP attenuated WAVE1-mediated actin polymerization, whereas preincubation with a protein phosphatase enhanced it. Striatal neurons from mice lacking WAVE1 showed a decrease in mature dendritic spines, as did cultured hippocampal neurons in which WAVE1 expression was inhibited with RNAi. Expression of an RNAi-resistant WAVE1 mutant reversed the effects of RNAi on spine morphology; a dephosphorylation-mimicking mutant had a greater effect than the wild-type mutant, whereas a phosphorylation-mimicking mutant had little effect. Treatment with a dopamine D1 receptor agonist or with forskolin (which stimulates adenylyl cyclase) decreased WAVE1 phosphorylation in striatal slices. Forskolin also decreased WAVE1 phosphorylation in cultured neurons and increased the number of mature dendritic spines (an effect that depended on WAVE1). Thus, the authors conclude that WAVE1 phosphorylation (by Cdk5) and dephosphorylation (in response to cAMP signaling) is likely involved in regulating the morphology of dendritic spines.
Y. Kim, J. Y. Sung, I. Ceglia, K.-W. Lee, J.-H. Ahn, J. M. Halford, A. M. Kim, S. P. Kwak, J. B. Park, S. H. Ryu, A. Schenck, B. Bardoni, J. D. Scott, A. C. Nairn, P. Greengard, Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology. Nature 442, 814-817 (2006). [PubMed]