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Cited by 117Genetics and Neurodevelopmental DisordersGenomic variations and chromosomal abnormalitiesAutism Spectrum Disorder Research

Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTor

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Oguro-Ando, A, Rosensweig, C, Herman, E, Nishimura, Y, Werling, D, Bill, B R, Berg, J M, Gao, F +3 more·2015·Molecular Psychiatry
DOI 10.1038/mp.2014.124PMC PMC4409498
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Abstract

Rare maternally inherited duplications at 15q11-13 are observed in ~1% of individuals with an autism spectrum disorder (ASD), making it among the most common causes of ASD. 15q11-13 comprises a complex region, and as this copy number variation encompasses many genes, it is important to explore individual genotype-phenotype relationships. Cytoplasmic FMR1-interacting protein 1 (CYFIP1) is of particular interest because of its interaction with Fragile X mental retardation protein (FMRP), its upregulation in transformed lymphoblastoid cell lines from patients with duplications at 15q11-13 and ASD and the presence of smaller overlapping deletions of CYFIP1 in patients with schizophrenia and intellectual disability. Here, we confirm that CYFIP1 is upregulated in transformed lymphoblastoid cell lines and demonstrate its upregulation in the post-mortem brain from 15q11-13 duplication patients for the first time. To investigate how increased CYFIP1 dosage might predispose to neurodevelopmental disease, we studied the consequence of its overexpression in multiple systems. We show that overexpression of CYFIP1 results in morphological abnormalities including cellular hypertrophy in SY5Y cells and differentiated mouse neuronal progenitors. We validate these results in vivo by generating a BAC transgenic mouse, which overexpresses Cyfip1 under the endogenous promotor, observing an increase in the proportion of mature dendritic spines and dendritic spine density. Gene expression profiling on embryonic day 15 suggested the dysregulation of mammalian target of rapamycin (mTOR) signaling, which was confirmed at the protein level. Importantly, similar evidence of mTOR-related dysregulation was seen in brains from 15q11-13 duplication patients with ASD. Finally, treatment of differentiated mouse neuronal progenitors with an mTOR inhibitor (rapamycin) rescued the morphological abnormalities resulting from CYFIP1 overexpression. Together, these data show that CYFIP1 overexpression results in specific cellular phenotypes and implicate modulation by mTOR signaling, further emphasizing its role as a potential convergent pathway in some forms of ASD.

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  • CYFIP1-overexpressing neurons and transgenic mice overexpressing CYFIP1 display immature dendritic spines.

    “CYFIP1-overexpressing neurons and transgenic mice overexpressing CYFIP1 display immature dendritic spines67,68.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [68]

    The Results section on spine morphology (page unavailable) reports the opposite for CYFIP1-overexpressing transgenic mice: one immature spine type was reduced by about 50%, while mature stubby spines increased. The in vitro Results report altered neurite morphology in CYFIP1-overexpressing neurons, not immature spines. (LLM, conf=0.91)

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  • This may lead to reassessment of the effect size of CYFIP1, which has been proposed as a large effect size neurodevelopmental gene.

    “This may lead to reassessment of the effect size of CYPFIP1, which has been proposed as a large effect size neurodevelopmental gene.12 13”

    From Estimating the effect size of the 15Q11.2 BP1–BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice (2019) · cites this paper as [13]

    The Discussion (page unavailable) describes CYFIP1 as having an important role in neurodevelopmental disease and reports pathological effects of increased dosage. It does not characterize CYFIP1 as a large-effect-size gene or estimate its effect size. The proposed reassessment is the citing authors’ own inference, not a finding attributed to this source. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • An increased level of Cyfip1 correlates with enhanced expression of mTor at the mRNA and protein levels.

    “It was shown that an increased level of Cyfip1 correlates with an enhanced expression of mTor (Oguro-Ando et al., 2015) at the mRNA and protein levels, suggesting a role of CYFIP1 in mRNA stability or, indirectly, transcriptional regulation.”

    From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Oguro-Ando et al., 2015

  • Overexpression of Cyfip1 produces an increased number of dendritic spines.

    “overexpression of Cyfip1 produces an increased number of dendritic spines (Oguro-Ando 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 Oguro-Ando et al., 2014

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Authors
Oguro-Ando, A., Rosensweig, C., Herman, E., Nishimura, Y., Werling, D., Bill, B. R., Berg, J. M., Gao, F., Coppola, G., Abrahams, B. S., & Geschwind, D. H.
Affiliations
  • University of California, Los Angeles (US)
  • Albert Einstein College of Medicine (US)
Corresponding author
Geschwind, D H
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2014-10-14
Volume
20
Issue
9
Pages
1069-1078
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/mp.2014.124
PMC
PMC4409498
OpenAlex
W2044692611
Cited by
117
References
22
Citations by year
2026: 4 · 2025: 7 · 2024: 10 · 2023: 6 · 2022: 7 · 2021: 13 · 2020: 10 · 2019: 10 · 2018: 24 · 2017: 4 · 2016: 12 · 2015: 10
FWCI
5.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Uehara Memorial Foundation
  • Intellectual and Developmental Disabilities Research Center
  • National Institute of Mental Health (R37MH60233-06A1, R01MH060233, R01MH081754-02R, R01MH081754, R37MH060233)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD071593)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords
CYFIP1, autism spectrum disorder, copy number variation, mTOR signaling, dendritic spine density, neuronal morphology, cell hypertrophy, FMRP, rapamycin, neuronal precursors, genotype-phenotype correlation
MeSH terms
Autism Spectrum Disorder, Animals, Cells, Cultured, Chromosomes, Human, Pair 15, Dendritic Cells, Female, Gene Expression Regulation, Humans, Mice, Inbred C57BL, Mice, Transgenic, Signal Transduction, Up-Regulation, Adaptor Proteins, Signal Transducing, Dendritic Spines, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1, DNA Copy Number Variations, TOR Serine-Threonine Kinases

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