Rho signaling and nervous system disorders
Accumulating data indicate that the Rho family of GTPases and their regulatory molecules play critical roles in many aspects of neuronal development. Given their importance in neuronal processes, it is therefore not surprising that mutations in genes encoding a number of regulators and effectors of the Rho-GTPases are associated with diseases affecting the nervous system. Aberrant Rho signaling has been shown to underlie various forms of mental retardation as well as defects in axon regeneration. We have been focusing on the functional characterization of Rho regulators and their involvement in neurological disorders. Among them, oligophrenin-1 (OPHN1) encodes a Rho-GAP and was the first Rho-linked MRX gene identified. Upon characterizing the localization of OPHN1, we found that the protein is expressed in neurons in major regions of the brain, including the hippocampus, cortex and cerebellum, and is present in axons, dendrites and dendritic spines. We obtained evidence for the requirement of OPHN1 in dendritic spine morphogenesis of hippocampal neurons. Using RNA interference and antisense approaches, we showed that knock-down of OPHN1 levels in CA1 pyramidal neurons in hippocampal slices results in a significant decrease in dendritic spine length, and that this spine length phenotype is mediated by the Rho/Rho-kinase pathway. In addition, we recently demonstrated a biochemical interaction between OPHN1 and Homer, a postsynaptic adaptor molecule involved in spine morphogenesis and synaptic transmission. An interaction between OPHN1 and Homer raises the intriguing possibility that OPHN1 acts downstream of glutamatergic receptors to regulate RhoA activity in spines, and thus spine morphogenesis. Together, these findings support the idea that cognitive deficits observed in human patients could be attributed to altered dendritic spine morphology.