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Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR

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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Acknowledgements

We would like to thank the UCLA transgenic mice core for injection of Cyfip1 Bac transgenic mice; Drs William Yang, Xiaofeng Gu, Paul Mischel, Akio Iwanami, Eric Wexler, Yoshitake Sano, Genevieve Konopka, Ezra Rosen and Luis de la Torre Ubieta for helpful discussions in planning the experiments; Drs Jeff Goodenbour, Jason Stein, Irina Voineagu, Olga Peñagarikano for important experimental advice and support; Greg Osborn, Hongmei Dong and Camille Fonseca for technical assistance and Lauren Kawaguchi for manuscript editing. This work was supported by funds from the Uehara Memorial Foundation (AO-A), Japan Society for the Promotion of Science (AO-A) and a New Investigator Development Award, a Human Genetics Pilot Award and a Rose F. Kennedy Intellectual and Developmental Disabilities Research Center (P30HD071593) Pilot Award from the Albert Einstein College of Medicine (BSA) and grants from the NIH (R37 MH60233-06A1, R01 MH081754-02R to DHG).

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Correspondence to D H Geschwind.

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The authors declare no conflict of interest. A provisional patent describing the potential utility of mTOR inhibitors in individuals with ASD harboring 15q11-13 duplications has been filed.

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Oguro-Ando, A., Rosensweig, C., Herman, E. et al. Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR. Mol Psychiatry 20, 1069–1078 (2015). https://doi.org/10.1038/mp.2014.124

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