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| Status |
Public on Mar 01, 2008 |
| Title |
Gene Expression Study in WT and ATF4 KO embryonic neurons |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Oxidative stress is pathogenic in neurological diseases including stroke. The identity of oxidative stress-inducible transcription factors and their role(s) in propagating the death cascade are poorly understood. Microarray analysis of neurons undergoing oxidative stress showed significant induction of prodeath genes. These genes have been shown to be regulated by the bZip transcription factor, ATF4. ATF4 protein localized to the promoter of a putative death gene in neurons in vitro and in vivo. Germline deletion of ATF4 in neurons resulted in a reduction in oxidative stress-induced gene expression and resistance to oxidative death. ATF4 knockout mice experienced significantly smaller infarcts and improved behavioral recovery as compared to wild-type mice subjected to the same reductions in blood flow in a rodent model of stroke. ATF4 modulates an early, upstream event in the death pathway, as resistance to oxidative death by ATF4 deletion was associated with decreased consumption of the antioxidant glutathione. Restoration of ATF4 protein in knockout neurons was sufficient to restore sensitivity to oxidative death and to reaccelerate loss of glutathione. Together, these findings establish ATF4 as a redox-regulated, pro-death transcriptional activator in the nervous system that propagates death responses to oxidative stress in vitro and to stroke in vivo.
Keywords: ATF4, oxidative stress, gene expression, neuroprotection, stroke
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| Overall design |
WT and ATF4 KO embryonic neurons were studied.
Untreated neurons (no=8 per genotype) and neurons challenged with oxidative stress with the glutamate homolog homocysteate (HCA, no=4 per genotype) were studied, for a total of 24 samples.
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| Contributor(s) |
Lange PS, Chavez JC, Pinto JT, Coppola G, Sun C, Townes TM, Geschwind DH, Ratan RR |
| Citation(s) |
18458112 |
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| Submission date |
Feb 11, 2008 |
| Last update date |
Jan 18, 2013 |
| 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) |
| GPL6100 |
Illumina mouseRef-8 v1.0 expression beadchip |
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| Samples (24)
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| Relations |
| BioProject |
PRJNA108031 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE10470_Microarray_raw_data.txt |
21.9 Mb |
(ftp)(http) |
TXT |
| GSE10470_RAW.tar |
2.6 Mb |
(http)(custom) |
TAR |
| Processed data included within Sample table |
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