Fragile X-like behaviors and abnormal cortical dendritic spines in cytoplasmic FMR1-interacting protein 2-mutant mice
Open accessAbstract
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.
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In Fmr1-knockout mice the Cyfip2+/− neuronal phenotype worsened.
“In Fmr1-knockout mice the Cyfip2+/− neuronal phenotype worsened (Han et al., 2015), while our data shows an antagonistic role of CYFIP1 and FMRP.”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Han et al., 2015
In “Abnormal cortical dendritic spines in Cyfip2 +/− mice,” the double mutants had a further increase in cortical protrusions and thin spines compared with Fmr1-null mice. The same section reports no further change in hippocampal dendritic protrusions, so the neuronal worsening is supported specifically for the cortical spine phenotype, not as a general neuronal phenotype. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDepletion of Cyfip1 has a different impact in different brain regions.
“or, alternatively, depletion of Cyfip1 has a different impact in different brain regions as also shown for Cyfip2 (Han et al., 2014).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Han et al., 2014
In mouse, CYFIP2 has been described both as a co-effector and a downstream target of FMRP.
“It is interesting to notice that in mouse, while we are describing CYFIP1 as an antagonist of FMRP, CYFIP2 has been described both as a co-effector (e.g. depletion of CYFIP2 worsens some phenotypes of Fmr1-knockout mouse) (Han et al., 2015) and a downstream target of FMRP.”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Han et al., 2015
Cyfip2 homozygous deletion is lethal in mice, indicating a vital role of CYFIP2 in early development.
“Cyfip2 homozygous deletion is lethal in mice, indicating the vital role of CYFIP2 in early development, whereas heterozygous KO mice exhibit abnormal behaviors and cortical dendritic spines, similar to those observed in Fmr1-null mice122.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [122]
Heterozygous Cyfip2 knockout mice exhibit abnormal behaviors and cortical dendritic spines, similar to those observed in Fmr1-null mice.
“Cyfip2 homozygous deletion is lethal in mice, indicating the vital role of CYFIP2 in early development, whereas heterozygous KO mice exhibit abnormal behaviors and cortical dendritic spines, similar to those observed in Fmr1-null mice122.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [122]
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The WAVE complex in developmental and adulthood brain disorders
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- Authors
- Han, K., Chen, H., Gennarino, V. A., Richman, R., Lu, H.-C., & Zoghbi, H. Y.
- Affiliations
- Howard Hughes Medical Institute (US)
- Texas Children's Hospital (US)
- Baylor College of Medicine (US)
- Corresponding author
- Han, Kihoon
- Zoghbi, Huda Y.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-11-28
- Volume
- 24
- Issue
- 7
- Pages
- 1813-1823
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC4355018
- OpenAlex
- W2097587720
- Cited by
- 72
- References
- 11
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 7 · 2023: 3 · 2022: 4 · 2021: 2 · 2020: 11 · 2019: 10 · 2018: 8 · 2017: 9 · 2016: 4 · 2015: 2
- FWCI
- 3.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS048884)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083092, P30HD024064)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- fragile X syndrome, CYFIP2, FMRP, FMR1 gene, dendritic spines, cortical neurons, metabotropic glutamate receptors, mRNA translation, WAVE regulatory complex, actin cytoskeleton, synaptic plasticity
- MeSH terms
- Animals, Behavior, Animal, Cerebral Cortex, Cytoplasm, Disease Models, Animal, Female, Fragile X Syndrome, Humans, Male, Mice, Inbred C57BL, Nerve Tissue Proteins, Mice, Knockout, Adaptor Proteins, Signal Transducing, Dendritic Spines, Mice, Fragile X Messenger Ribonucleoprotein 1, Fragile X Mental Retardation Protein
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