Neuron-specific SUMO knockdown suppresses global gene expression response and worsens functional outcome after transient forebrain ischemia in mice
| Autor: | Huaxin Sheng, Ying Li, Wulf Paschen, Xiaozhi Liu, Shuai Liu, David S. Warner, Lin Zhang, Wei Yang, Julia Q. Zhao |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Blotting Western SUMO protein Fluorescent Antibody Technique Motor Activity Biology Real-Time Polymerase Chain Reaction Severity of Illness Index Neuroprotection Article Brain Ischemia 03 medical and health sciences Prosencephalon 0302 clinical medicine microRNA Gene expression Animals Mice Knockout Neurons Regulation of gene expression Gene knockdown Microscopy Confocal Arc (protein) Microarray analysis techniques General Neuroscience Recovery of Function Microarray Analysis Molecular biology Cell biology Mice Inbred C57BL Disease Models Animal 030104 developmental biology Gene Expression Regulation Small Ubiquitin-Related Modifier Proteins 030217 neurology & neurosurgery |
| Zdroj: | Neuroscience. 343:190-212 |
| ISSN: | 0306-4522 |
| Popis: | Small ubiquitin-like modifier (SUMO) conjugation (SUMOylation) plays key roles in neurologic function in health and disease. Neuronal SUMOylation is essential for emotionality and cognition, and this pathway is dramatically activated in post-ischemic neurons, a neuroprotective response to ischemia. It is also known from cell culture studies that SUMOylation modulates gene expression. However, it remains unknown how SUMOylation regulates neuronal gene expression in vivo, in the physiologic state and after ischemia, and modulates post-ischemic recovery of neurologic function. To address these important questions, we used a SUMO1-3 knockdown (SUMO-KD) mouse in which a Thy-1 promoter drives expression of 3 distinct microRNAs against SUMO1-3 to silence SUMO expression specifically in neurons. Wild-type and SUMO-KD mice were subjected to transient forebrain ischemia. Microarray analysis was performed in hippocampal CA1 samples, and neurologic function was evaluated. SUMOylation had opposite effects on neuronal gene expression before and after ischemia. In the physiological state, most genes regulated by SUMOylation were up-regulated in SUMO-KD compared to wild-type mice. Brain ischemia/reperfusion significantly modulated the expression levels of more than 400 genes in wild-type mice, with a majority of those genes upregulated. The extent of this post-ischemic transcriptome change was suppressed in SUMO-KD mice. Moreover, SUMO-KD mice exhibited significantly worse functional outcome. This suggests that suppression of global gene expression response in post-ischemic brain due to SUMO knockdown has a negative effect on post-ischemic neurologic function. Together, our data provide a basis for future studies to mechanistically link SUMOylation to neurologic function in health and disease. |
| Databáze: | OpenAIRE |
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