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

Kihoon Han, Hogmei Chen, Vincenzo A. Gennarino, Ronald Richman, Hui Chen Lu, Huda Y. Zoghbi

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)


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 spineswere normal in Cyfip2+/- hippocampus. However, dendritic spines were altered in Cyfip2+/- cortex, and the dendritic spine phenotype of Fmr1-/y cortexwas aggravated in Fmr1-/y; Cyfip2+/- doublemutant 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.

Original languageEnglish
Pages (from-to)1813-1823
Number of pages11
JournalHuman Molecular Genetics
Issue number7
Publication statusPublished - 2014 Oct 28
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by The Howard Hughes Medical Institute (to H.Y.Z.); and the Baylor Intellectual and Developmental Disabilities Research Center (P30HD024064) confocal, electrophysiology and mouse neurobehavioral cores.

Publisher Copyright:
© The Author 2014. Published by Oxford University Press.

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Fragile X-like behaviors and abnormal cortical dendritic spines in Cytoplasmic FMR1-interacting protein 2-mutant mice'. Together they form a unique fingerprint.

Cite this