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

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

doi:10.1074/jbc.m703298200

Abstract

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.

Highlights

The p21-activated kinase 3 (PAK3)2 is one of these recently identified genes implicated in X-linked nonsyndromic forms of mental retardation, and three mutations have been identified in independent families [7,8,9]
We show that the two mutations R419X and A365E completely inactivate the catalytic function of the kinase
Differential Effects of PAK3 Mental Retardation Mutations on Its Kinase Activity—The three mutations responsible for mental retardation are located in different functional regions of the PAK3 protein (Fig. 1A)

Summary

Introduction

The p21-activated kinase 3 (PAK3)2 is one of these recently identified genes implicated in X-linked nonsyndromic forms of mental retardation, and three mutations have been identified in independent families [7,8,9]. Whereas the mutated proteins are normally localized in dendritic spines, their expression in hippocampal neurons of organotypic slice cultures induces different phenotypes.

Results

Conclusion