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

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. 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. The number, shape, and structure of dendritic spines change in response to synaptic activity, and anomalies of spine morphogenesis are often associated with cognitive defects, such as mental retardation, Alzheimer disease, Down syndrome, autism, and schizophrenia (1Purpura D.P. Science. 1974; 186: 1126-1128Crossref PubMed Scopus (424) Google Scholar, 2Fiala J.C. Spacek J. Harris K.M. Brain Res. Brain Res. Rev. 2002; 39: 29-54Crossref PubMed Scopus (669) Google Scholar). Actin cytoskeleton, enriched in dendritic spines, plays a major role in spine dynamics and is under the control of Rho-GTPase signaling (3Matus A. Science. 2000; 290: 754-758Crossref PubMed Scopus (666) Google Scholar, 4Govek E.E. Newey S.E. Van Aelst L. Genes Dev. 2005; 19: 1-49Crossref PubMed Scopus (772) Google Scholar, 5Tada T. Sheng M. Curr. Opin. Neurobiol. 2006; 16: 95-101Crossref PubMed Scopus (522) Google Scholar). Several genes that are implicated in nonsyndromic mental retardation are direct regulators or effectors of Rho GTPases (6Van Galen E.J.M. Ramakers G.J. Prog. Brain Res. 2005; 147: 295-317Crossref PubMed Scopus (67) Google Scholar). The p21-activated kinase 3 (PAK3) 2The abbreviations used are: PAK, p21-activated kinase; PBD, p21-binding domain; GFP, green fluorescent protein; EGFP, enhanced GFP; mRFP, monomeric red fluorescent protein; DIV, days in vitro; MBP, myelin basic protein; GEF, guanine exchange factor; HA, hemagglutinin; CMV, cytomegalovirus; siRNA, small interference RNA. 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 (7Allen K.M. Gleeson J.G. Bagrodia S. Partington M.W. MacMillan J.C. Cerione R.A. Mulley J.C. Walsh C.A. Nat. Genet. 1998; 20: 25-30Crossref PubMed Scopus (392) Google Scholar, 8Bienvenu T. des Portes V. McDonell N. Carrie A. Zemni R. Couvert P. Ropers H.H. Moraine C. van Bokhoven H. Fryns J.P. Allen K. Walsh C.A. Boue J. Kahn A. Chelly J. Beldjord C. Am. J. Med. Genet. 2000; 93: 294-298Crossref PubMed Scopus (112) Google Scholar, 9Gedeon A.K. Nelson J. Gecz J. Mulley J.C. Am. J. Med. Genet. 2003; 120A: 509-517Crossref PubMed Scopus (58) Google Scholar). PAK3 is a member of the PAKs group I, which are effectors of Rac1 and Cdc42 GTPases. Interestingly, inhibition of PAKs by expression of an inhibitory peptide in postnatal forebrains impaired synaptic plasticity (10Hayashi M.L. Choi S.Y. Rao B.S. Jung H.Y. Lee H.K. Zhang D. Chattarji S. Kirkwood A. Tonegawa S. Neuron. 2004; 42: 773-787Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar). PAKs also play a fundamental role in cognitive deficits in Alzheimer disease (11McPhie D.L. Coopersmith R. Hines-Peralta A. Chen Y. Ivins K.J. Manly S.P. Kozlowski M.R. Neve K.A. Neve R.L. J. Neurosci. 2003; 23: 6914-6927Crossref PubMed Google Scholar, 12Zhao L. Ma Q.L. Calon F. Harris-White M.E. Yang F. Lim G.P. Morihara T. Ubeda O.J. Ambegaokar S. Hansen J.E. Weisbart R.H. Teter B. Frautschy S.A. Cole G.M. Nat. Neurosci. 2006; 9: 234-242Crossref PubMed Scopus (268) Google Scholar). Recent evidence supports a role for PAKs in spine morphogenesis: indeed inhibition of PAKs decreased the number of spines and altered their morphology (10Hayashi M.L. Choi S.Y. Rao B.S. Jung H.Y. Lee H.K. Zhang D. Chattarji S. Kirkwood A. Tonegawa S. Neuron. 2004; 42: 773-787Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar). Concerning PAK3, reduction of its expression or expression of a PAK3 kinase-dead mutant induced abnormal elongated dendritic spines and decreased mature spine synapses (13Boda B. Alberi S. Nikonenko I. Node-Langlois R. Jourdain P. Moosmayer M. Parisi-Jourdain L. Muller D. J. Neurosci. 2004; 24: 10816-10825Crossref PubMed Scopus (147) Google Scholar, 14Zhang H. Webb D.J. Asmussen H. Niu S. Horwitz A.F. J. Neurosci. 2005; 25: 3379-3388Crossref PubMed Scopus (282) Google Scholar). PAK3 knockdown and knock-out experiments induce abnormal long term potentiation, indicating a major role for PAK3 in synaptic plasticity (13Boda B. Alberi S. Nikonenko I. Node-Langlois R. Jourdain P. Moosmayer M. Parisi-Jourdain L. Muller D. J. Neurosci. 2004; 24: 10816-10825Crossref PubMed Scopus (147) Google Scholar, 15Meng J. Meng Y. Hanna A. Janus C. Jia Z. J. Neurosci. 2005; 25: 6641-6650Crossref PubMed Scopus (150) Google Scholar). How PAK3 regulates spinogenesis and synaptic plasticity is still unknown. To address this question, we introduced the three identified mental retardation mutations into the PAK3 gene and analyzed their effects on the functions of PAK3. Two mutations, R419X and A365E, are located in the kinase domain, whereas the third one, R67C, is present in the regulatory domain, at the N-terminal end of the p21-GTPase-binding domain (PBD). We show that the two mutations R419X and A365E completely inactivate the catalytic function of the kinase. We also report that Cdc42 is the main activator of PAK3 and that the R67C mutation severely impairs PAK3 binding to Cdc42 and the subsequent activation of PAK3. Interestingly, whereas the mutated proteins are normally localized in dendritic spines, their expression in hippocampal neurons of organotypic slice cultures induces different phenotypes. Our data delineate a new pathway linking the Cdc42 GTPase to PAK3 in dendritic spine morphogenesis. Antibodies—Antibodies to HA (12CA5) were purchased from Roche Diagnostics (Meylan, France). The anti-PAK3-N19 antibody directed against the 19 N-terminal amino acids and the GFP antibody were purchased from Santa Cruz Biotechnology (Tebu, Le Perray the and the were purchased from the and were from PAK3 were from the PAK3 as PAK3 V. N. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). of the PAK3 mutants were from the V. N. J. 2003; Full Text Full Text PDF PubMed Scopus Google with the The and by The mutations introduced into PAK3 the three mutations responsible for mental R67C and to the A365E and to the R419X and to the The PAK3 mutant with the and to the The the mutation to a kinase V. N. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The of the different PAK3 were into the to PAK3 and The by to the domain, from from J. The The into the expression expression the or to the domain were by into from J. The GTPase in GFP and were by P. and in the the were to of GTPases. The for the domain, by J. of of The red fluorescent a from C. and a from and for and and of were as V. N. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). expression to to cultures of hippocampal neurons were from as by and K. Asmussen H. 1998; Scholar). were at days in and at at to the The spines that the of mature in these we in spines, in the spine and show synaptic S. M. P. N. J. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). of the used to the of spines in and GFP or mutant PAK3 expression were at a of with a the of an and the of a for of GFP or and neurons were and were with a dendritic spines often we of from the to the of and used to and organotypic hippocampal slice cultures were as by L. Muller D. J. Neurosci. PubMed Scopus Google Scholar). were days in and a gene to the at a of of to of were of of slice and expression experiments that with and green and red in Two days hippocampal organotypic cultures were in a with an and with and of of dendritic a experiments that under the morphology or of of to dendritic were on and of and the of dendritic were The analyzed were and and from the of the to the of the and were as V. N. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). to the of were with of in the of at were by with of antibody and of at the were to to that proteins were and were by and to a France). the France). of with a and proteins were in and on as by the kinase were one more in the kinase were in the kinase and of for at in the or in the of 3 of or 3 of myelin basic as a in the and the were by The of a as V. N. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). were with of Rac1 or Cdc42 with of PAK3 in were with were by and to with to PAK3, (12CA5) to and to Cdc42 or Rac1 and from to to the Cdc42 and Rac1 in or were as V. N. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). were on for 3 days at The were with as the to the by and to by to the number of The of with to were three in of PAK3 on three mutations responsible for mental retardation are located in different of the PAK3 The located in the catalytic domain, a at the for to a which is of kinase (7Allen K.M. Gleeson J.G. Bagrodia S. Partington M.W. MacMillan J.C. Cerione R.A. Mulley J.C. Walsh C.A. Nat. Genet. 1998; 20: 25-30Crossref PubMed Scopus (392) Google Scholar). The in the kinase domain, to a of a to a A.K. Nelson J. Gecz J. Mulley J.C. Am. J. Med. Genet. 2003; 120A: 509-517Crossref PubMed Scopus (58) Google Scholar). The third mutation present at the of the domain the to a T. des Portes V. McDonell N. Carrie A. Zemni R. Couvert P. Ropers H.H. Moraine C. van Bokhoven H. Fryns J.P. Allen K. Walsh C.A. Boue J. Kahn A. Chelly J. Beldjord C. Am. J. Med. Genet. 2000; 93: 294-298Crossref PubMed Scopus (112) Google Scholar). The associated with the A365E and R67C mutations have been To the effects of the three mutations R419X, A365E, and R67C, on the of PAK3, we introduced into the of the PAK3 We these new mutated forms to two the kinase-dead mutant and a binding mutant Bagrodia S. G.M. J. Curr. Full Text Full Text PDF PubMed Scopus Google Scholar, A. S. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). To their kinase activity, the different PAK3 mutants were in with or forms of Cdc42. were with PAK3 proteins the as The PAK3 is activated with whereas is with the of the GTPase. the and the proteins kinase activity. We also report here that the A365E mutation completely the kinase of PAK3. the the kinase as the with with by these results We activation of PAK3 and were with to the R419X and A365E which are of kinase activity, the kinase of the R67C mutant is to that of the PAK3 in these PAK3 Cdc42 than its activation Cdc42 the of the R67C at the of the that this mutation the binding of PAK3 to the GTPases and its We the of or Rac1 and Cdc42 to the PAK3 a We that forms of Rac1 and Cdc42 PAK3 and We also that the impaired in GTPase with or in the PAK3 with the Cdc42 the with the of Rac1 is of the PAK3 and Cdc42. of these different are in data To that the PAK3 binds more Cdc42 than with forms of and were and were analyzed for the of the associated GTPases the of proteins with the GTPases by we used kinase-dead mutants of PAK3 J. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). of GTPases that the of Cdc42 to PAK3 is than Rac1 with Rac1 of the with The R67C Cdc42 to analyzed the of the with Rac1 and Cdc42 GTPases the and Interestingly, we show that the R67C mutation decreased the binding of PAK3 to Cdc42 decreased to with the with PAK3. However, the binding of to Rac1 significantly different from and To this we GTPase with PAK3 proteins from We that and the and with the we a decrease of the of Cdc42 with to However, in these binds more Rac1 than the PAK3 and We also analyzed by the of Cdc42 with the three kinase-dead mutants and We that these mutations the binding of PAK3 with this GTPase in with the of the of PAK3 with Cdc42 (7Allen K.M. Gleeson J.G. Bagrodia S. Partington M.W. MacMillan J.C. Cerione R.A. Mulley J.C. Walsh C.A. Nat. Genet. 1998; 20: 25-30Crossref PubMed Scopus (392) Google Scholar, C. T. C. Lim L. J. Full Text Full Text PDF PubMed Scopus Google Scholar). results demonstrate that PAK3 binds Cdc42 more than Rac1 and that the R67C mutation significantly decreased the binding of PAK3 to Cdc42 and the binding to R67C by the R67C is activated is in the with this GTPase is and by the expression of which the of of for To more control the of Cdc42 used to PAK3, we an in kinase by of to of or were Cdc42 or with a of the kinase in is significantly activated by than the under these To the in activation of PAK3 by endogenous Cdc42 and we of the of the guanine exchange and to specific activation of Cdc42 and F. J.C. van R.A. J.G. PubMed Scopus Google Scholar, S. M. S. M. S.E. N. Nat. PubMed Scopus Google Scholar). We the of the by the of Cdc42 and Rac1 in a to GTPases. The of an in endogenous of but whereas the expression of the of and to a The activation of Rac1 by is to an endogenous activation of Rac1 by Cdc42 A. H. van J. T. R. K. C. 2005; 16: PubMed Scopus Google Scholar). To the activation of PAK3 by and we kinase with the The results were with the We that the of PAK3 with the of induced an of its kinase activity. Interestingly, the activated in these and However, the expression of the of PAK3 or R67C mutant and results that PAK3 is activated by the module and that the R67C which the binding of PAK3 to Cdc42, impairs PAK3 the R67C mutation the binding of PAK3 to Rac1 an activation of PAK3 by the the main of the R67C is its of activation by Cdc42 to a decrease of its to this GTPase. PAK3 PAK3 in PAK3 is in neurons (7Allen K.M. Gleeson J.G. Bagrodia S. Partington M.W. MacMillan J.C. Cerione R.A. Mulley J.C. Walsh C.A. Nat. Genet. 1998; 20: 25-30Crossref PubMed Scopus (392) Google Scholar, B. Alberi S. Nikonenko I. Node-Langlois R. Jourdain P. Moosmayer M. Parisi-Jourdain L. Muller D. J. Neurosci. 2004; 24: 10816-10825Crossref PubMed Scopus (147) Google Scholar, Brain Res. 2002; PubMed Scopus Google and have its in dendritic spines (10Hayashi M.L. Choi S.Y. Rao B.S. Jung H.Y. Lee H.K. Zhang D. Chattarji S. Kirkwood A. Tonegawa S. Neuron. 2004; 42: 773-787Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar, Chen J. Neurosci. PubMed Scopus Google we the that PAK3 mutations induce a of the in dendritic spines of been that expression of a kinase-dead PAK3 in hippocampal neurons induces a in dendritic spine formation H. Webb D.J. Asmussen H. Niu S. Horwitz A.F. J. Neurosci. 2005; 25: 3379-3388Crossref PubMed Scopus (282) Google Scholar). we also a decrease in spine in neurons the kinase-dead mutant and this of spine of PAK3 recently been that the of in hippocampal organotypic of neurons spine Brain Res. 2006; PubMed Scopus Google Scholar). we to the inhibition of spinogenesis induced by the expression of mutated PAK3 proteins and we the of PAK3 proteins in PAK3 or mutants were in hippocampal neurons with the The expression of also the of the morphology of dendritic spines in these the expression of the kinase-dead mutant dendritic spine formation We a of in the dendritic and in the of spines, with The three kinase-dead proteins R419X, and A365E and the two mutants GTPase and R67C, the as the these we or in the spine morphology and density. We that the kinase and the binding to GTPases are for PAK3 spine and that the PAK3 mutations alter the of the to of PAK3 analyzed the effects of these different PAK3 mutants in of hippocampal organotypic slice a that is to the in for of spine morphogenesis. R419X, A365E, and R67C mutants were with in Two were analyzed the of dendritic and and from the of the to the of the We the expression of proteins in neurons by HA as in and with results (13Boda B. Alberi S. Nikonenko I. Node-Langlois R. Jourdain P. Moosmayer M. Parisi-Jourdain L. Muller D. J. Neurosci. 2004; 24: 10816-10825Crossref PubMed Scopus (147) Google expression of PAK3 the R419X kinase-dead mutation in a by a of spines and an in elongated spines and (13Boda B. Alberi S. Nikonenko I. Node-Langlois R. Jourdain P. Moosmayer M. Parisi-Jourdain L. Muller D. J. Neurosci. 2004; 24: 10816-10825Crossref PubMed Scopus (147) Google Scholar). the but significantly in these with neurons and the in in the of elongated of Interestingly, expression of the A365E mutant a to the R419X with a slightly different the two of in the reduction in more in than been with the R419X mutation whereas the in elongated as by the in the of and expression of the R67C which the in a reduction in the spine and in spine and in the of spine these the of and were expression of the mental retardation PAK3 mutants the of spine morphogenesis. PAK3 for of the PAK3 to and are and is the of mutated genes associated with mental retardation J. Nat. Rev. Genet. PubMed Scopus Google Scholar). the and of mental retardation mutations is a the that are for cognitive functions. We report here the of three PAK3 proteins mutations responsible for mental retardation, and we show that these mutations PAK3 functions. The two mutations R419X and A365E, located in the catalytic domain inactivate the kinase activity. for the but for the A365E mutant (7Allen K.M. Gleeson J.G. Bagrodia S. Partington M.W. MacMillan J.C. Cerione R.A. Mulley J.C. Walsh C.A. Nat. Genet. 1998; 20: 25-30Crossref PubMed Scopus (392) Google Scholar, 9Gedeon A.K. Nelson J. Gecz J. Mulley J.C. Am. J. Med. Genet. 2003; 120A: 509-517Crossref PubMed Scopus (58) Google Scholar). A365E mutation is located in a the of the of the 2003; PubMed Scopus Google Scholar). Several mutations associated with were identified in this the C. J. K. M. 2005; 25: PubMed Scopus Google Scholar). We report here for the that a mutation in this the kinase activity. The is in the PAK3 gene of in and genes is also present in the two PAKs of the group in and in in and and to a in is located in the of the from to and the domain from to G.M. Rev. 2003; PubMed Scopus Google Scholar). Several mutations in the domain the binding to Rac1 and Cdc42 Chen C. T. Lim L. 1998; PubMed Google Scholar). in the of the have mutations of three and decrease the Rac1 but Cdc42, and activation by Cdc42 and Rac1 G.M. J. 1998; PubMed Scopus Google Scholar). their mutation to basic been that the of in different GTPase effectors plays an role in Cdc42 M. Meng 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). this we show that the R67C mutation decreases the with Cdc42 as a the activation by Cdc42. We have that R67C mutation the binding to whereas the mutation the of PAK3 with this GTPase in we is that the of Cdc42 binding to PAK3 induce an of Rac1 this mutation the binding to induce the activation of PAK3 by a specific for is in with data that the binding of GTPases to is to activation G.M. J. 1998; PubMed Scopus Google Scholar). Our results show that the of the PAK3 by a role in the the and the GTPases. the R67C mutation is responsible for a more than the two mutations of PAK3 suggesting that the of PAK3 with Cdc42 is for synaptic plasticity. PAK3 have such as a role A. S. C. Lim L. J. 1998; PubMed Scopus Google and on Cdc42 Cdc42 the of to activated by Cdc42 and Rac1 GTPases C. T. C. Lim L. J. Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. Cerione R.A. J. Full Text Full Text PDF PubMed Scopus Google Scholar). with we that of PAK3 with or induced a activation of the kinase. However, we activated PAK3 by endogenous we that Cdc42 to PAK3. a specific for Cdc42, activated PAK3 the endogenous Cdc42 whereas a specific for The endogenous activation by the GTPase expression in the which the of PAK3 for We report here that the PAK3 binds Cdc42 and which is in with the that GTPase is for activation T. H. Lim L. PubMed Scopus Google Scholar). we that the mental retardation R67C mutation its activation by the pathway that the Cdc42/PAK3 module is the one implicated in cognitive functions. PAK3 of the PAK3 PAK3 mutations induce a of PAK3 responsible for synaptic defects, we analyzed the of the mental retardation PAK3 mutants in mature Interestingly, we demonstrate here that of the kinase-dead PAK3 mutants in spine and dendritic suggesting that spine is independent of kinase activity. However, the of PAK3, in dendritic spines by and of (10Hayashi M.L. Choi S.Y. Rao B.S. Jung H.Y. Lee H.K. Zhang D. Chattarji S. Kirkwood A. Tonegawa S. Neuron. 2004; 42: 773-787Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar, 14Zhang H. Webb D.J. Asmussen H. Niu S. Horwitz A.F. J. Neurosci. 2005; 25: 3379-3388Crossref PubMed Scopus (282) Google Scholar). we that PAK3 is for We also show that with GTPases is for spine the R67C mutant and the proteins the as the PAK3 to spines with such as the H. Webb D.J. Asmussen H. Niu S. Horwitz A.F. J. Neurosci. 2005; 25: 3379-3388Crossref PubMed Scopus (282) Google Scholar). To we demonstrate for the that mental retardation PAK3 mutations induce in spines, suggesting that cognitive in mental retardation associated with PAK3 mutations, are to a of PAK3. of a Cdc42/PAK3 in that the kinase of PAK3 is for the formation of mature dendritic spines (13Boda B. Alberi S. Nikonenko I. Node-Langlois R. Jourdain P. Moosmayer M. Parisi-Jourdain L. Muller D. J. Neurosci. 2004; 24: 10816-10825Crossref PubMed Scopus (147) Google Scholar, 14Zhang H. Webb D.J. Asmussen H. Niu S. Horwitz A.F. J. Neurosci. 2005; 25: 3379-3388Crossref PubMed Scopus (282) Google Scholar). of and in hippocampal organotypic slice in the formation of abnormal spines, with a decrease of mature dendritic spines and an in (13Boda B. Alberi S. Nikonenko I. Node-Langlois R. Jourdain P. Moosmayer M. Parisi-Jourdain L. Muller D. J. Neurosci. 2004; 24: 10816-10825Crossref PubMed Scopus (147) Google Scholar). We report here that expression of the kinase-dead mutant induced a whereas expression of in Cdc42 binding and in activation by Cdc42, to a decrease of spine density. these results show that of the kinase and and of binding and activation by Cdc42 to spine suggesting that PAK3 binding to Cdc42 and PAK3 kinase are for The R67C mutation affects spine suggesting that this mutation alter different in spine number spine or of Concerning the the present anomalies or as the spine is However, we such and we the that the R67C mutation impairs spine We a in which PAK3 at two different spine at the of spines and at spine The binding of Cdc42 to PAK3 to the formation of a signaling in the of the of new is that Cdc42 formation in and PAK3 is implicated in we that Cdc42 formation the activation of PAK3 J. K. Curr. Opin. 2006; PubMed Scopus Google Scholar). the the kinase for the and of as also by the small of the on spines (13Boda B. Alberi S. Nikonenko I. Node-Langlois R. Jourdain P. Moosmayer M. Parisi-Jourdain L. Muller D. J. Neurosci. 2004; 24: 10816-10825Crossref PubMed Scopus (147) Google Scholar). The elongated in neurons kinase-dead mutants to of spines in spine and a in a R. T. Nat. Rev. Neurosci. 2004; PubMed Scopus Google Scholar). The role of Cdc42 in spine formation is poorly E.E. Newey S.E. Van Aelst L. Genes Dev. 2005; 19: 1-49Crossref PubMed Scopus (772) Google Scholar, 5Tada T. Sheng M. Curr. Opin. Neurobiol. 2006; 16: 95-101Crossref PubMed Scopus (522) Google Scholar). However, in to PAK3, Cdc42 effectors implicated in spine morphogenesis such as or J. J. B. A. Lee S. M. Lee K. J. Neurosci. 2005; 25: PubMed Scopus Google Scholar, F. Y. Nat. Neurosci. 2002; PubMed Scopus Google Scholar). The of Cdc42 in the PAK3 signaling pathway in spine or and Cdc42 been effectors than PAK3 also However, a PAK3 mutant such as the R67C mutant we selectively in Cdc42 a to the role of Cdc42/PAK3 module in The of regulators and of the Cdc42/PAK3 module of major to this pathway regulates synaptic plasticity and is impaired in mental retardation associated in with mental retardation, the of PAK3 function is by the the of a specific role of PAK3 in synaptic plasticity. The of these functions a to the signaling of plasticity. We and for for in two for in hippocampal and for with the of and and of the We also and for on the with