Stroke target identification guided by astrocyte transcriptome analysis
| Autor: | Thomas Ulas, Toni Schumacher, Walker S. Jackson, Khalid Tai, Melvin Schleif, Joachim L. Schultze, Cordula Rakers, Santiago Valle Torres, Hana Matuskova, Kristian Händler, Gabor C. Petzold, Nelli Blank |
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| Jazyk: | angličtina |
| Předmět: |
0301 basic medicine
Male Galectin 3 genetics [Luminescent Proteins] genetics [Galectin 3] genetics [Gene Expression Regulation] Pathogenesis Transcriptome Mice 0302 clinical medicine metabolism [STAT3 Transcription Factor] Stroke metabolism [Astrocytes] Stat3 protein mouse Neurodegeneration pathology [Rhombencephalon] Infarction Middle Cerebral Artery Astrogliosis pathology [Infarction Middle Cerebral Artery] medicine.anatomical_structure Neurology physiopathology [Infarction Middle Cerebral Artery] Female Astrocyte STAT3 Transcription Factor Ischemia metabolism [Lipocalin-2] Mice Transgenic Nerve Tissue Proteins Biology Neuroprotection 03 medical and health sciences Cellular and Molecular Neuroscience Lipocalin-2 medicine Animals Immunoprecipitation ddc:610 metabolism [Luminescent Proteins] metabolism [Nerve Tissue Proteins] Gene Expression Profiling genetics [Lipocalin-2] metabolism [Galectin 3] Computational Biology genetics [STAT3 Transcription Factor] medicine.disease metabolism [Connexin 43] Rhombencephalon Mice Inbred C57BL Disease Models Animal Luminescent Proteins 030104 developmental biology Gene Expression Regulation Astrocytes Rotarod Performance Test Connexin 43 genetics [Connexin 43] Neuroscience 030217 neurology & neurosurgery methods [Gene Expression Profiling] |
| Zdroj: | Glia 67(4), 619-633 (2018). doi:10.1002/glia.23544 Glia |
| ISSN: | 0894-1491 |
| DOI: | 10.1002/glia.23544 |
| Popis: | Astrocytes support normal brain function, but may also contribute to neurodegeneration when they become reactive under pathological conditions such as stroke. However, the molecular underpinnings of this context‐dependent interplay between beneficial and detrimental properties in reactive astrogliosis have remained incompletely understood. Therefore, using the RiboTag technique, we immunopurified translating mRNAs specifically from astrocytes 72 hr after transient middle cerebral artery occlusion in mice (tMCAO), thereby generating a stroke‐specific astroglial translatome database. We found that compared to control brains, reactive astrocytes after tMCAO show an enrichment of transcripts linked to the A2 phenotype, which has been associated with neuroprotection. However, we found that astrocytes also upregulate a large number of potentially neurotoxic genes. In total, we identified the differential expression of 1,003 genes and 38 transcription factors, of which Stat3, Sp1, and Spi1 were the most prominent. To further explore the effects of Stat3‐mediated pathways on stroke pathogenesis, we subjected mice with an astrocyte‐specific conditional deletion of Stat3 to tMCAO, and found that these mice have reduced stroke volume and improved motor outcome 72 hr after focal ischemia. Taken together, our study extends the emerging database of novel astrocyte‐specific targets for stroke therapy, and supports the role of astrocytes as critical safeguards of brain function in health and disease. (Less) |
| Databáze: | OpenAIRE |
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