title: Fragile X-like behaviors and abnormal cortical dendritic spines in cytoplasmic FMR1-interacting protein 2-mutant mice.
abstract: Silencing of fragile X mental retardation 1 (FMR1) gene and loss of fragile X mental retardation protein (FMRP) cause fragile X syndrome (FXS), a genetic disorder characterized by intellectual disability and autistic behaviors. FMRP is an mRNA-binding protein regulating neuronal translation of target mRNAs. Abnormalities in actin-rich dendritic spines are major neuronal features in FXS, but the molecular mechanism and identity of FMRP targets mediating this phenotype remain largely unknown. Cytoplasmic FMR1-interacting protein 2 (Cyfip2) was identified as an interactor of FMRP, and its mRNA is a highly ranked FMRP target in mouse brain. Importantly, Cyfip2 is a component of WAVE regulatory complex, a key regulator of actin cytoskeleton, suggesting that Cyfip2 could be implicated in the dendritic spine phenotype of FXS. Here, we generated and characterized Cyfip2-mutant (Cyfip2(+/-)) mice. We found that Cyfip2(+/-) mice exhibited behavioral phenotypes similar to Fmr1-null (Fmr1(-/y)) mice, an animal model of FXS. Synaptic plasticity and dendritic spines were normal in Cyfip2(+/-) hippocampus. However, dendritic spines were altered in Cyfip2(+/-) cortex, and the dendritic spine phenotype of Fmr1(-/y) cortex was aggravated in Fmr1(-/y); Cyfip2(+/-) double-mutant mice. In addition to the spine changes at basal state, metabotropic glutamate receptor (mGluR)-induced dendritic spine regulation was impaired in both Fmr1(-/y) and Cyfip2(+/-) cortical neurons. Mechanistically, mGluR activation induced mRNA translation-dependent increase of Cyfip2 in wild-type cortical neurons, but not in Fmr1(-/y) or Cyfip2(+/-) neurons. These results suggest that misregulation of Cyfip2 function and its mGluR-induced expression contribute to the neurobehavioral phenotypes of FXS.
authors.affiliation: Department of Molecular and Human Genetics, The Howard Hughes Medical Institute, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA kihoonh@bcm.edu hzoghbi@bcm.edu.
authors.forename: Kihoon
authors.initials: K
authors.lastname: Han
authors.affiliation: Departments of Pediatrics and, The Cain Foundation Laboratories Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Hogmei
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Molecular and Human Genetics, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Vincenzo A
authors.initials: VA
authors.lastname: Gennarino
authors.affiliation: Department of Molecular and Human Genetics, The Howard Hughes Medical Institute, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Richman
authors.affiliation: Departments of Pediatrics and, Program in Developmental Biology and Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA, The Cain Foundation Laboratories Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Lu
authors.affiliation: Department of Molecular and Human Genetics, The Howard Hughes Medical Institute, Departments of Pediatrics and, Program in Developmental Biology and Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA kihoonh@bcm.edu hzoghbi@bcm.edu.
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000002:abnormalities / Q000378:metabolism*; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; C529497:Cyfip2 protein, mouse