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Fragile X-like behaviors and abnormal cortical dendritic spines in cytoplasmic FMR1-interacting protein 2-mutant mice
Kihoon Han1, Hogmei Chen2, Vincenzo A Gennarino3
1Department 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.
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.
Insights
Fragile X syndrome (FXS) involves FMR1 gene silencing. Researchers found that misregulation of Cyfip2 protein contributes to FXS neurobehavioral and dendritic spine abnormalities, offering new insights into the disorder.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Fragile X syndrome (FXS) results from FMR1 gene silencing and FMRP loss, causing intellectual disability and autistic behaviors.
- Abnormalities in dendritic spines are a hallmark of FXS, but the underlying molecular mechanisms and FMRP targets are not fully understood.
- Cytoplasmic FMR1-interacting protein 2 (Cyfip2) interacts with FMRP and regulates the actin cytoskeleton, suggesting a role in FXS pathophysiology.
Purpose of the Study:
- To investigate the role of Cyfip2 in the neurobehavioral and synaptic phenotypes associated with Fragile X syndrome.
- To determine if Cyfip2 dysfunction contributes to the dendritic spine abnormalities observed in FXS.
Main Methods:
- Generation and characterization of Cyfip2-mutant (Cyfip2(+/-)) mice.
- Behavioral analysis of Cyfip2(+/-) and Fmr1-null (Fmr1(-/y)) mice, including double mutants.
- Analysis of synaptic plasticity and dendritic spine morphology in hippocampal and cortical neurons.
- Investigation of metabotropic glutamate receptor (mGluR)-induced dendritic spine regulation and Cyfip2 expression.
Main Results:
- Cyfip2(+/-) mice exhibited behavioral phenotypes mirroring Fmr1(-/y) mice.
- Dendritic spines were altered in the cortex of Cyfip2(+/-) mice and aggravated in double mutants.
- mGluR-induced dendritic spine regulation was impaired in both Fmr1(-/y) and Cyfip2(+/-) cortical neurons.
- mGluR activation failed to increase Cyfip2 expression in Fmr1(-/y) or Cyfip2(+/-) neurons.
Conclusions:
- Misregulation of Cyfip2 contributes to the neurobehavioral and dendritic spine phenotypes in a mouse model of FXS.
- Impaired mGluR-induced Cyfip2 expression is a key mechanism linking FMRP loss to synaptic dysfunction in FXS.
- Targeting Cyfip2 may offer therapeutic potential for Fragile X syndrome.
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