Publication Date:
2015-03-12
Description:
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.
Print ISSN:
0964-6906
Electronic ISSN:
1460-2083
Topics:
Biology
,
Medicine
Permalink