title: 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.
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.|Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Oguro-Ando
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Rosensweig
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Herman
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Nishimura
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Werling
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: B R
authors.initials: BR
authors.lastname: Bill
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Berg
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Gao
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.|Semel Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Coppola
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: B S
authors.initials: BS
authors.lastname: Abrahams
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.|Department of Human Genetics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Geschwind
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002884:Chromosomes, Human, Pair 15; D056915:DNA Copy Number Variations; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D049229:Dendritic Spines / Q000235:genetics / Q000473:pathology; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051860:Fragile X Messenger Ribonucleoprotein 1; D058570:TOR Serine-Threonine Kinases; C109916:CYFIP1 protein, human; C546842:MTOR protein, human