PMID- 25311365
OWN - NLM
STAT- MEDLINE
DCOM- 20160607
LR  - 20220309
IS  - 1476-5578 (Electronic)
IS  - 1359-4184 (Print)
IS  - 1359-4184 (Linking)
VI  - 20
IP  - 9
DP  - 2015 Sep
TI  - Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates 
      mTOR.
PG  - 1069-78
LID - 10.1038/mp.2014.124 [doi]
AB  - 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.
FAU - Oguro-Ando, A
AU  - Oguro-Ando A
AD  - 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.
AD  - Department of Translational Neuroscience, Brain Center Rudolf Magnus, University 
      Medical Center Utrecht, Utrecht, The Netherlands.
FAU - Rosensweig, C
AU  - Rosensweig C
AD  - 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.
FAU - Herman, E
AU  - Herman E
AD  - 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.
FAU - Nishimura, Y
AU  - Nishimura Y
AD  - 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.
FAU - Werling, D
AU  - Werling D
AD  - 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.
FAU - Bill, B R
AU  - Bill BR
AD  - 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.
FAU - Berg, J M
AU  - Berg JM
AD  - 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.
FAU - Gao, F
AU  - Gao F
AD  - 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.
FAU - Coppola, G
AU  - Coppola G
AD  - 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.
AD  - Semel Institute, David Geffen School of Medicine, University of California at Los 
      Angeles, Los Angeles, CA, USA.
FAU - Abrahams, B S
AU  - Abrahams BS
AD  - 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.
FAU - Geschwind, D H
AU  - Geschwind DH
AD  - 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.
AD  - Department of Human Genetics, David Geffen School of Medicine, University of 
      California at Los Angeles, Los Angeles, CA, USA.
LA  - eng
GR  - P30HD071593/HD/NICHD NIH HHS/United States
GR  - R01 MH081754-02R/MH/NIMH NIH HHS/United States
GR  - R37 MH060233/MH/NIMH NIH HHS/United States
GR  - R01 MH060233/MH/NIMH NIH HHS/United States
GR  - P30 HD071593/HD/NICHD NIH HHS/United States
GR  - R37 MH60233-06A1/MH/NIMH NIH HHS/United States
GR  - R01 MH081754/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20141014
PL  - England
TA  - Mol Psychiatry
JT  - Molecular psychiatry
JID - 9607835
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (CYFIP1 protein, human)
RN  - 139135-51-6 (Fragile X Mental Retardation Protein)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/biosynthesis/*genetics/metabolism
MH  - Animals
MH  - Autism Spectrum Disorder/genetics/metabolism/pathology
MH  - Cells, Cultured
MH  - Chromosomes, Human, Pair 15
MH  - DNA Copy Number Variations
MH  - Dendritic Cells/metabolism/pathology/*physiology
MH  - Dendritic Spines/genetics/pathology
MH  - Female
MH  - Fragile X Mental Retardation Protein/genetics/metabolism
MH  - Gene Expression Regulation
MH  - Humans
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
MH  - Up-Regulation
PMC - PMC4409498
MID - NIHMS659804
EDAT- 2014/10/15 06:00
MHDA- 2016/06/09 06:00
PMCR- 2015/12/01
CRDT- 2014/10/15 06:00
PHST- 2014/04/13 00:00 [received]
PHST- 2014/07/18 00:00 [revised]
PHST- 2014/08/21 00:00 [accepted]
PHST- 2014/10/15 06:00 [entrez]
PHST- 2014/10/15 06:00 [pubmed]
PHST- 2016/06/09 06:00 [medline]
PHST- 2015/12/01 00:00 [pmc-release]
AID - mp2014124 [pii]
AID - 10.1038/mp.2014.124 [doi]
PST - ppublish
SO  - Mol Psychiatry. 2015 Sep;20(9):1069-78. doi: 10.1038/mp.2014.124. Epub 2014 Oct 
      14.