WAVE1—the Wiskott–Aldrich syndrome protein (WASP)-family verprolin homologous protein 1—is a key regulator of actin-dependent morphological processes1 in mammals, through its ability to activate the actin-related protein (Arp2/3) complex. Here we show that WAVE1 is phosphorylated at multiple sites by cyclin-dependent kinase 5 (Cdk5) both in vitro and in intact mouse neurons. Phosphorylation of WAVE1 by Cdk5 inhibits its ability to regulate Arp2/3 complex-dependent actin polymerization. Loss of WAVE1 function in vivo or in cultured neurons results in a decrease in mature dendritic spines. Expression of a dephosphorylation-mimic mutant of WAVE1 reverses this loss of WAVE1 function in spine morphology, but expression of a phosphorylation-mimic mutant does not. Cyclic AMP (cAMP) signalling reduces phosphorylation of the Cdk5 sites in WAVE1, and increases spine density in a WAVE1-dependent manner. Our data suggest that phosphorylation/dephosphorylation of WAVE1 in neurons has an important role in the formation of the filamentous actin cytoskeleton, and thus in the regulation of dendritic spine morphology.
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Stradal, T. E. et al. Regulation of actin dynamics by WASP and WAVE family proteins. Trends Cell Biol. 14, 303–311 (2004)
Smith, D. S., Greer, P. L. & Tsai, L. H. Cdk5 on the brain. Cell Growth Differ. 12, 277–283 (2001)
Cruz, J. C. & Tsai, L. H. A Jekyll and Hyde kinase: roles for Cdk5 in brain development and disease. Curr. Opin. Neurobiol. 14, 390–394 (2004)
Bibb, J. A. et al. Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature 402, 669–671 (1999)
Patrick, G. N. et al. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402, 615–622 (1999)
Bibb, J. A. et al. Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature 410, 376–380 (2001)
Norrholm, S. D. et al. Cocaine-induced proliferation of dendritic spines in nucleus accumbens is dependent on the activity of cyclin-dependent kinase-5. Neuroscience 116, 19–22 (2003)
Eden, S., Rohatgi, R., Podtelejnikov, A. V., Mann, M. & Kirschner, M. W. Mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck. Nature 418, 790–793 (2002)
Suetsugu, S., Miki, H. & Takenawa, T. Identification of two human WAVE/SCAR homologues as general actin regulatory molecules which associate with the Arp2/3 complex. Biochem. Biophys. Res. Commun. 260, 296–302 (1999)
Takenawa, T. & Miki, H. WASP and WAVE family proteins: key molecules for rapid rearrangement of cortical actin filaments and cell movement. J. Cell Sci. 114, 1801–1809 (2001)
Innocenti, M. et al. Abi1 is essential for the formation and activation of a WAVE2 signalling complex. Nature Cell Biol. 6, 319–327 (2004)
Irie, F. & Yamaguchi, Y. EphB receptors regulate dendritic spine development via intersectin, Cdc42 and N-WASP. Nature Neurosci. 5, 1117–1118 (2002)
Grove, M. et al. ABI2-deficient mice exhibit defective cell migration, aberrant dendritic spine morphogenesis, and deficits in learning and memory. Mol. Cell. Biol. 24, 10905–10922 (2004)
Choi, J. et al. Regulation of dendritic spine morphogenesis by insulin receptor substrate 53, a downstream effector of Rac1 and Cdc42 small GTPases. J. Neurosci. 25, 869–879 (2005)
Rao, A. & Craig, A. M. Signaling between the actin cytoskeleton and the postsynaptic density of dendritic spines. Hippocampus 10, 527–541 (2000)
Miki, H., Suetsugu, S. & Takenawa, T. WAVE, a novel WASP-family protein involved in actin reorganization induced by Rac. EMBO J. 17, 6932–6941 (1998)
Luo, L. et al. Differential effects of the Rac GTPase on Purkinje cell axons and dendritic trunks and spines. Nature 379, 837–840 (1996)
Nakayama, A. Y., Harms, M. B. & Luo, L. Small GTPases Rac and Rho in the maintenance of dendritic spines and branches in hippocampal pyramidal neurons. J. Neurosci. 20, 5329–5338 (2000)
Soderling, S. H. et al. Loss of WAVE-1 causes sensorimotor retardation and reduced learning and memory in mice. Proc. Natl Acad. Sci. USA 100, 1723–1728 (2003)
Matus, A. Actin-based plasticity in dendritic spines. Science 290, 754–758 (2000)
Saito, T. et al. Developmental regulation of the proteolysis of the p35 cyclin-dependent kinase 5 activator by phosphorylation. J. Neurosci. 23, 1189–1197 (2003)
Nishi, A., Snyder, G. L. & Greengard, P. Bidirectional regulation of DARPP-32 phosphorylation by dopamine. J. Neurosci. 17, 8147–8155 (1997)
Dahl, J. P. et al. Characterization of the WAVE1 knock-out mouse: implications for CNS development. J. Neurosci. 23, 3343–3352 (2003)
Lee, K.-W. et al. Cocaine-induced dendritic spine formation in D1 and D2 dopamine receptor-containing medium spiny neurons in nucleus accumbens. Proc. Natl Acad. Sci. USA 103, 3399–3404 (2006)
Machesky, L. M. et al. Scar, a WASp-related protein, activates nucleation of actin filaments by the Arp2/3 complex. Proc. Natl Acad. Sci. USA 96, 3739–3744 (1999)
We thank W.-B. Gan for assisting us with the DiI staining method; L.-H. Tsai for providing P35 cDNA; A. Yamamoto for Nap1 cDNA; and P. Aspenström for N-WASP antibody. We also thank T. D. Pollard for suggestions. This work was supported by the postdoctoral fellowship programme of the Korea Science & Engineering Foundation (KOSEF) (to J.Y.S.), and funding from the F.M. Kirby foundation (to P.G.), the Picower Foundation (to P.G.), the National Institute of Mental Health, the National Institute of Drug Abuse and the National Institute on Aging (to A.C.N. and P.G.). Author Contributions Y.K., J.Y.S., I.C. and K.-W.L. performed experiments; J.M.H. and A.M.K. assisted in experiments; J.-H.A., S.P.K., A.S., B.B. and J.D.S. provided reagents; J.B.P. and S.H.R. performed MALDI-TOF mass spectrometry; Y.K., A.C.N. and P.G. designed experiments and wrote the manuscript.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
This file contains Supplementary Figures and Legends 1–7, Supplementary Table 1 and Supplementary Methods. The Supplementary Figures show the interaction of P35 with the WAVE complex, phosphorylation of WAVE1, actin polymerization catalyzed by WAVE1 and Cdk5 activity in striatal slices following forskolin treatment. The Supplementary Table provides stoichiometry of phosphorylation of WAVE1. The Supplementary Methods provide technical details of experimental methods used in this study. (PDF 622 kb)
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Kim, Y., Sung, J., Ceglia, I. et al. Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology. Nature 442, 814–817 (2006). https://doi.org/10.1038/nature04976
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