title: The X-linked mental retardation protein oligophrenin-1 is required for dendritic spine morphogenesis.
abstract: Of 11 genes involved in nonspecific X-linked mental retardation (MRX), three encode regulators or effectors of the Rho GTPases, suggesting an important role for Rho signaling in cognitive function. It remains unknown, however, how mutations in Rho-linked genes lead to MRX. Here we report that oligophrenin-1, a Rho-GTPase activating protein that is absent in a family affected with MRX, is required for dendritic spine morphogenesis. Using RNA interference and antisense RNA approaches, we show that knock-down of oligophrenin-1 levels in CA1 neurons in rat hippocampal slices significantly decreases spine length. This phenotype can be recapitulated using an activated form of RhoA and rescued by inhibiting Rho-kinase, indicating that reduced oligophrenin-1 levels affect spine length by increasing RhoA and Rho-kinase activities. We further demonstrate an interaction between oligophrenin-1 and the postsynaptic adaptor protein Homer. Our findings provide the first insight into how mutations in a Rho-linked MRX gene may compromise neuronal function.
authors.affiliation: Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.
authors.forename: Eve-Ellen
authors.initials: EE
authors.lastname: Govek
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Newey
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Akerman
authors.forename: Justin R
authors.initials: JR
authors.lastname: Cross
authors.forename: Lieven
authors.initials: L
authors.lastname: Van der Veken
authors.forename: Linda
authors.initials: L
authors.lastname: Van Aelst
mesh_terms: D000818:Animals; D048429:Cell Size / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism; D015536:Down-Regulation; D020690:GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D038901:X-Linked Intellectual Disability / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009024:Morphogenesis; D016501:Neurites / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009924:Organ Culture Techniques; D034622:RNA Interference / Q000502:physiology; D016372:RNA, Antisense / Q000502:physiology; D051381:Rats; D013569:Synapses / Q000378:metabolism*; D014162:Transfection
chemical_list: D003598:Cytoskeletal Proteins; D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; C498439:Ophn1 protein, mouse; D016372:RNA, Antisense