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Title

Sequential implication of the mental retardation proteins ARHGEF6 and PAK3 in spine morphogenesis

Authors
Nodé-Langlois, Roxanne
Published in Journal of Cell Science. 2006, vol. 119, no. Pt 23, p. 4986-4993
Abstract The biological mechanisms underlying the mental retardation associated with mutation of the ARHGEF6 gene, a Rac1/Cdc42 exchange factor, are still unknown, although defects in the plasticity of synaptic networks have been postulated. We have cloned the rat ARHGEF6 gene and investigated, using a transfection approach, its involvement in spine morphogenesis and its relationship to p21-activated kinase 3 (PAK3). We found that expression of tagged ARHGEF6 in hippocampal slice cultures shows a punctate staining in dendritic spines that colocalizes with PSD95. Over-expression of ARHGEF6, of PAK3 or constitutively active PAK3 did not alter spine morphology. By contrast, knockdown of ARHGEF6 using a siRNA approach resulted in abnormalities in spine morphology similar to those reported with knockdown of PAK3. This phenotype could be rescued through co-expression of a constitutively active PAK3 protein, but not with wild-type PAK3. Together, these results indicate that ARHGEF6 is localized in dendritic spines where it contributes to regulate spine morphogenesis probably by acting through a downstream activation of PAK3. Similar mechanisms are thus likely to underlie the mental retardation induced by mutations of ARHGEF6 and PAK3.
Keywords AnimalsCell Cycle Proteins/antagonists & inhibitors/genetics/metabolism/ physiologyDendritic Spines/ genetics/metabolismGuanine Nucleotide Exchange Factors/antagonists &Inhibitors/genetics/metabolism/ physiologyHippocampus/cytology/metabolismMental Retardation/geneticsMiceNIH 3T3 CellsPhenotypeProtein-Serine-Threonine Kinases/antagonists &Inhibitors/genetics/metabolism/ physiologyRNA, Small Interfering/pharmacologyRatsTime FactorsTissue Culture TechniquesTransfectionP21-Activated Kinases
Stable URL http://archive-ouverte.unige.ch/unige:10376
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PMID: 17105769
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