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J. Biol. Chem., Vol. 282, Issue 29, 21497-21506, July 20, 2007

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The p21-activated Kinase 3 Implicated in Mental Retardation Regulates Spine Morphogenesis through a Cdc42-dependent Pathway^*

Patricia Kreis, Emmanuel Thévenot, Véronique Rousseau, Bernadett Boda, Dominique Muller, and Jean-Vianney Barnier¹

From the CNRS, Institut de Neurobiologie Alfred Fessard, FRC2118, Laboratoire de Neurobiologie Cellulaire et Moléculaire, UPR9040, 1 avenue de la terrasse, Gif sur Yvette, F-91198, France and the Department of Basic Neuroscience, Centre Medical Universitaire, 1211 Geneva 4, Switzerland

The p21-activated kinase 3 (PAK3) is one of the recently identified genes for which mutations lead to nonsyndromic mental retardation. PAK3 is implicated in dendritic spine morphogenesis and is a key regulator of synaptic functions. However, the underlying roles of PAK3 in these processes remain poorly understood. We report here that the three mutations R419X, A365E, and R67C, responsible for mental retardation have different effects on the biological functions of PAK3. The R419X and A365E mutations completely abrogate the kinase activity. The R67C mutation drastically decreases the binding of PAK3 to the small GTPase Cdc42 and impairs its subsequent activation by this GTPase. We also report that PAK3 binds significantly more Cdc42 than Rac1 and is selectively activated by endogenous Cdc42, suggesting that PAK3 is a specific effector of Cdc42. Interestingly, the expression of the three mutated proteins in hippocampal neurons affects spinogenesis differentially. Both kinase-dead mutants slightly decrease the number of spines but profoundly alter spine morphology, whereas expression of the R67C mutant drastically decreases spine density. These results demonstrate that the Cdc42/PAK3 is a key module in dendritic spine formation and synaptic plasticity.

Received for publication, April 19, 2007 , and in revised form, May 29, 2007.

^* This work was supported in part by grants from CNRS, Fondation Jérôme Lejeune, Association contre le Cancer, Ligue contre le Cancer-Essonne, Fédération pour la Recherche sur le Cerveau, by a fellowship from Fondation pour la Recherche Médicale (to P. K.), and by grants from the Swiss National Science Foundation, Telethon and Eagle Foundation (to D. M.). The Barnier team is a member of the CNRS research network GDR2823. 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-S3.

¹ To whom correspondence should be addressed: Tel.: 33-1-69823418; Fax: 33-1-69824141; E-mail: barnier{at}nbcm.cnrs-gif.fr.

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