Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR

A. Oguro-Ando, C. Rosensweig, E. Herman, Y. Nishimura, D. Werling, B. R. Bill, J. M. Berg, F. Gao, G. Coppola, B. S. Abrahams, D. H. Geschwind

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1069-1078
Number of pages10
JournalMolecular Psychiatry
Volume20
Issue number9
DOIs
StatePublished - Sep 24 2015

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Sirolimus
Proteins
Dendritic Spines
Transformed Cell Line
Up-Regulation
Fragile X Mental Retardation Protein
Phenotype
Brain
Gene Expression Profiling
Intellectual Disability
Hypertrophy
Transgenic Mice
Schizophrenia
Genotype
Autism Spectrum Disorder
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Oguro-Ando, A., Rosensweig, C., Herman, E., Nishimura, Y., Werling, D., Bill, B. R., ... Geschwind, D. H. (2015). Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR. Molecular Psychiatry, 20(9), 1069-1078. https://doi.org/10.1038/mp.2014.124

Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR. / 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.

In: Molecular Psychiatry, Vol. 20, No. 9, 24.09.2015, p. 1069-1078.

Research output: Contribution to journalArticle

Oguro-Ando, A, Rosensweig, C, Herman, E, Nishimura, Y, Werling, D, Bill, BR, Berg, JM, Gao, F, Coppola, G, Abrahams, BS & Geschwind, DH 2015, 'Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR', Molecular Psychiatry, vol. 20, no. 9, pp. 1069-1078. https://doi.org/10.1038/mp.2014.124
Oguro-Ando A, Rosensweig C, Herman E, Nishimura Y, Werling D, Bill BR et al. Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR. Molecular Psychiatry. 2015 Sep 24;20(9):1069-1078. https://doi.org/10.1038/mp.2014.124
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. / Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR. In: Molecular Psychiatry. 2015 ; Vol. 20, No. 9. pp. 1069-1078.
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