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

J Cell Sci. 2006 Dec 1;119(Pt 23):4986-93. doi: 10.1242/jcs.03273. Epub 2006 Nov 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Cycle Proteins / physiology*
  • Dendritic Spines / genetics*
  • Dendritic Spines / metabolism
  • Guanine Nucleotide Exchange Factors / antagonists & inhibitors
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism
  • Guanine Nucleotide Exchange Factors / physiology*
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Intellectual Disability / genetics
  • Mice
  • NIH 3T3 Cells
  • Phenotype
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Serine-Threonine Kinases / physiology*
  • RNA, Small Interfering / pharmacology
  • Rats
  • Rho Guanine Nucleotide Exchange Factors
  • Time Factors
  • Tissue Culture Techniques
  • Transfection
  • p21-Activated Kinases


  • Arhgef6 protein, mouse
  • Cell Cycle Proteins
  • Guanine Nucleotide Exchange Factors
  • RNA, Small Interfering
  • Rho Guanine Nucleotide Exchange Factors
  • arhgef6 protein, rat
  • Pak3 protein, mouse
  • Pak3 protein, rat
  • Protein Serine-Threonine Kinases
  • p21-Activated Kinases