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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jan 01, 2015 |
| Title |
Overexpression of disease-associated CYFIP1 alters cellular and synaptic morphology through mTOR dysregulation of mTOR signaling |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Rare 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.
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| Overall design |
Mice harboring a Cyfip1 spanning BAC clone (RP24-333C15) were generated in the UCLA transgenic core (http://tmc.ctrl.ucla.edu/tg-core/) by injection into C57BL/6J pronuclei. Transgenic mice were identified by PCR screening of tail derived DNA.
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| Contributor(s) |
Oguro-Ando A, Rosensweig C, Herman E, Nishimura Y, Werling D, Bill B, Berg J, Gao F, Coppola G, Abrahams B, Geschwind D |
| Citation(s) |
25311365 |
| Submission date |
Sep 13, 2012 |
| Last update date |
Jun 14, 2018 |
| Contact name |
Giovanni Coppola |
| E-mail(s) |
gcoppola@ucla.edu
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| Phone |
310-794-4172
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| Organization name |
UCLA
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| Department |
Psychiatry and Neurology
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| Lab |
Neurogenetics
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| Street address |
1524 Gonda, 695 Charles Young Drive South
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| City |
Los Angeles |
| State/province |
CA |
| ZIP/Postal code |
90095 |
| Country |
USA |
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| Platforms (1) |
| GPL6885 |
Illumina MouseRef-8 v2.0 expression beadchip |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA175113 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE40852_RAW.tar |
3.1 Mb |
(http)(custom) |
TAR |
| GSE40852_matrix_non-normalized_data.txt.gz |
726.7 Kb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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