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Nature 442, 814-817 (17 August 2006) | doi:10.1038/nature04976; Received 18 April 2006; Accepted 6 June 2006; Published online 16 July 2006

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Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology

Yong Kim1, Jee Young Sung1, Ilaria Ceglia1, Ko-Woon Lee1, Jung-Hyuck Ahn1, Jonathan M. Halford1, Amie M. Kim1, Seung P. Kwak2, Jong Bae Park3, Sung Ho Ryu3, Annette Schenck4, Barbara Bardoni4, John D. Scott5, Angus C. Nairn1,6 & Paul Greengard1

  1. Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA
  2. Discovery Neurosciences, Wyeth Research, Princeton, New Jersey 08543, USA
  3. Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, 790-784, Korea
  4. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, BP 10142, 67404 Illkirch cedex, France
  5. Howard Hughes Medical Institute, Vollum Institute, 3181 Sam Jackson Park Road, Portland, Oregon 97239-3098, USA
  6. Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, Connecticut 06508, USA

Correspondence to: Paul Greengard1 Correspondence and requests for materials should be addressed to Y.K. (Email: kimyo@rockefeller.edu), A.C.N. (Email: angus.nairn@yale.edu) and P.G. (Email: greengard@rockefeller.edu).

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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.