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J. Biol. Chem., Vol. 283, Issue 23, 15912-15920, June 6, 2008

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N-WASP and the Arp2/3 Complex Are Critical Regulators of Actin in the Development of Dendritic Spines and Synapses^*

Adam M. Wegner, Caroline A. Nebhan, Lan Hu, Devi Majumdar, Kristen M. Meier, Alissa M. Weaver^¶, and Donna J. Webb^¶1

From the Neuroscience Graduate Program, Department of Biological Sciences and Vanderbilt Kennedy Center for Research on Human Development, and ^¶Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37235

Changes in the number, size, and shape of dendritic spines are associated with synaptic plasticity, which underlies cognitive functions such as learning and memory. This plasticity is attributed to reorganization of actin, but the molecular signals that regulate this process are poorly understood. In this study, we show neural Wiskott-Aldrich syndrome protein (N-WASP) regulates the formation of dendritic spines and synapses in hippocampal neurons. N-WASP localized to spines and active, functional synapses as shown by loading with FM4–64 dye. Knock down of endogenous N-WASP expression by RNA interference or inhibition of its activity by treatment with a specific inhibitor, wiskostatin, caused a significant decrease in the number of spines and excitatory synapses. Deletion of the C-terminal VCA region of N-WASP, which binds and activates the actin-related protein 2/3 (Arp2/3) complex, dramatically decreased the number of spines and synapses, suggesting activation of the Arp2/3 complex is critical for spine and synapse formation. Consistent with this, Arp3, like N-WASP, was enriched in spines and excitatory synapses and knock down of Arp3 expression impaired spine and synapse formation. A similar defect in spine and synapse formation was observed when expression of an N-WASP activator, Cdc42, was knocked down. Thus, activation of N-WASP and, subsequently, the Arp2/3 complex appears to be an important molecular signal for regulating spines and synapses. Arp2/3-mediated branching of actin could be a mechanism by which dendritic spine heads enlarge and subsequently mature. Collectively, our results point to a critical role for N-WASP and the Arp2/3 complex in spine and synapse formation.

Received for publication, February 26, 2008 , and in revised form, April 16, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant MH071674 (to D. J. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S5.

¹ To whom correspondence should be addressed: VU Station B, Box 35-1634, Nashville, TN 37235. Tel.: 615-936-8274; Fax: 615-343-6707; E-mail: donna.webb{at}vanderbilt.edu.

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