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 journalArticle

31 Citations (Scopus)

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 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
Article numberddu595
Pages (from-to)1813-1823
Number of pages11
JournalHuman Molecular Genetics
Volume24
Issue number7
DOIs
Publication statusPublished - 2014 Jan 1
Externally publishedYes

Fingerprint

Fragile X Mental Retardation Protein
Dendritic Spines
Fragile X Syndrome
Proteins
Metabotropic Glutamate Receptors
Phenotype
Protein Biosynthesis
Neurons
Intellectual Disability
Messenger RNA
Inborn Genetic Diseases
Neuronal Plasticity
Mutant Proteins
Actin Cytoskeleton
Actins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Fragile X-like behaviors and abnormal cortical dendritic spines in Cytoplasmic FMR1-interacting protein 2-mutant mice. / Han, Kihoon; Chen, Hogmei; Gennarino, Vincenzo A.; Richman, Ronald; Lu, Hui Chen; Zoghbi, Huda Y.

In: Human Molecular Genetics, Vol. 24, No. 7, ddu595, 01.01.2014, p. 1813-1823.

Research output: Contribution to journalArticle

Han, Kihoon ; Chen, Hogmei ; Gennarino, Vincenzo A. ; Richman, Ronald ; Lu, Hui Chen ; Zoghbi, Huda Y. / Fragile X-like behaviors and abnormal cortical dendritic spines in Cytoplasmic FMR1-interacting protein 2-mutant mice. In: Human Molecular Genetics. 2014 ; Vol. 24, No. 7. pp. 1813-1823.
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