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| Status |
Public on Sep 01, 2011 |
| Title |
Functional Genomic Analyses Identify Pathways Dysregulated by Progranulin Deficiency Implicating Wnt Signaling |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Progranulin (GRN) mutations cause frontotemporal dementia (FTD), but GRN's function in the CNS remains largely unknown. To identify the pathways downstream of GRN, we used weighted genome co-expression network analysis (WGCNA) to develop a systems-level view of transcriptional alterations in a human neural progenitor model of GRN-deficiency. This highlighted key pathways such as apoptosis and ubiquitination in GRN deficient human neurons, while revealing an unexpected major role for the Wnt signaling pathway, which was confirmed by analysis of gene expression data from postmortem FTD brain. Furthermore, we observed that the Wnt receptor Fzd2 was one of only a few genes up-regulated at 6 weeks in a GRN knockout mouse, and that FZD2 reduction caused increased apoptosis, while its upregulation promoted neuronal survival in vitro. Together, these in vitro and in vivo data point to an adaptive role for altered Wnt signaling in GRN deficiency-mediated FTD, representing a potential therapeutic target.
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| Overall design |
We therefore developed an in vitro model of GRN deficiency using primary human neural stem cells in which shRNA was used to diminish GRN levels to 50% or below. We developed a tetracycline inducible system in which transactivator protein rtTA3 and PuroR genes were constituitively expressed under the UBC promoter, while RFP and shRNA were regulated by an inducible tet-On CMV promoter (Gossen and Bujard, 1992). To control for off-target effects, two hairpins against GRN were used, and a scrambled hairpin was used as a control.
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| Contributor(s) |
Rosen EY, Wexler EM, Versano R, Coppola G, Gao F, Winden KD, Oldham MC, Herl L, Zhou P, Farese RV, Geschwind DH |
| Citation(s) |
21943601 |
| Submission date |
Aug 31, 2011 |
| Last update date |
Mar 20, 2017 |
| 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) |
| GPL6883 |
Illumina HumanRef-8 v3.0 expression beadchip |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA145273 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE31772_RAW.tar |
3.9 Mb |
(http)(custom) |
TAR |
| GSE31772_non-normalized.txt.gz |
1.2 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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