Overexpression of disease-associated CYFIP1 alters cellular and synaptic morphology through mTOR dysregulation of mTOR signaling
Transcriptomics Dataset
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General Information
AccessionGSE40852
TitleOverexpression of disease-associated CYFIP1 alters cellular and synaptic morphology through mTOR dysregulation of mTOR signaling
DescriptionRare genomic gains at 15q11-q13 are observed in 1-2%% of individuals with an Autism Spectrum Disorder (ASD). Because many genes are included here and breakpoints vary between cases, the potential contribution of specific genes is unclear. Cytoplasmic FMR1 interacting protein 1 (CYFIP1) is interesting in this regard given the association of smaller overlapping deletions with each of schizophrenia and intellectual disability. Towards an understanding of how increased CYFIP1 dosage might predispose to neurodevelopmental disease we investigated the consequence of overexpression in multiple systems. We show that CYFIP1 mRNA is increased in lymphoblastoid cells and human brain as a function of 15q dosage. Towards mechanisms, we determined that overexpression of CYFIP1 results in cellular abnormalities in SY5Y cells and mouse neuronal progenitors. Identical abnormalities, as well as anomalies in synaptic morphology, were seen after comparing two BAC transgenic strains to controls. Gene expression profiling at embryonic day 15 identified genes differentially expressed between transgenic and control mice and highlighted dysregulation of mTOR signaling. Finally, treatment of mouse neuronal progenitors with an mTOR inhibitor (Rapamycin) rescued morphologic abnormalities resulting from CYFIP1 overexpression. Together, these data are consistent with the notion that normalization of mTOR signaling, emerging as an important point of convergence in the ASDs, may be of clinical utility in genetically selected populations with a variety of neurodevelopmental disorders.
Landing Pagehttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE40852
RepositoryGene Expression Omnibus
Tools used to analyze the dataset
Keyword
Dataset Accession
Enrichr
Published May 2016
A comprehensive gene set enrichment analysis web server 2016 update
7759
65
Characteristic Direction
Published March 2014
A geometrical multivariate approach to identify differentially expressed genes
26829
GeneMANIA
Published June 2010
Biological network integration for gene prioritization and predicting gene function
7435
L1000CDS2
Published August 2016
An ultra-fast LINCS L1000 Characteristic Direction signature search engine
7756
PAEA
Published November 2015
Enrichment analysis tool implementing the principal angle method
3879
Canned Analyses generated with the dataset
Filters  
Dataset Accession
Tool Name
Direction
Geneset
Small molecules which mimic CYFIP1 OE
L1000CDS2, Characteristic Direction
The L1000 database was queried in order to identify small molecule perturbations which mim...
Small molecules which reverse CYFIP1 OE
L1000CDS2, Characteristic Direction
The L1000 database was queried in order to identify small molecule perturbations which rev...
Enrichment analysis of genes dysregulated in CYFIP1 OE
PAEA, Characteristic Direction
An enrichment analysis was performed on the top most dyresgulated genes determined by appl...
Interaction network and enrichment analysis of genes downregulated in CYFIP1 OE
GeneMANIA, Characteristic Direction
The analysis explores the gene interaction network and pathway enrichment of the top 50 mo...
Interaction network and enrichment analysis of genes upregulated in CYFIP1 OE
GeneMANIA, Characteristic Direction
The analysis explores the gene interaction network and pathway enrichment of the top 50 mo...
Enrichment analysis of genes downregulated in CYFIP1 OE
Enrichr, Characteristic Direction
An enrichment analysis was performed on the top 500 most downregulated genes identified by...
Enrichment analysis of genes upregulated in CYFIP1 OE
Enrichr, Characteristic Direction
An enrichment analysis was performed on the top 500 most upregulated genes identified by a...
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