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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.

Fragile X-like behaviors and abnormal cortical dendritic spines in Cytoplasmic FMR1-interacting protein 2 -mutant mice