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Neuron-specific SUMO knockdown suppresses global gene expression response and worsens functional outcome after transient forebrain ischemia in mice.

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Date
2017-02
Authors
Zhang, Lin
Liu, Xiaozhi
Sheng, Huaxin
Liu, Shuai
Li, Ying
Zhao, Julia Q
Warner, David S
Paschen, Wulf
Yang, Wei
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Abstract
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.
Type
Journal article
Subject
Prosencephalon
Neurons
Animals
Mice, Inbred C57BL
Mice, Knockout
Brain Ischemia
Disease Models, Animal
Small Ubiquitin-Related Modifier Proteins
Microscopy, Confocal
Fluorescent Antibody Technique
Blotting, Western
Microarray Analysis
Severity of Illness Index
Motor Activity
Recovery of Function
Gene Expression Regulation
Real-Time Polymerase Chain Reaction
Permalink
https://hdl.handle.net/10161/23256
Published Version (Please cite this version)
10.1016/j.neuroscience.2016.11.036
Publication Info
Zhang, Lin; Liu, Xiaozhi; Sheng, Huaxin; Liu, Shuai; Li, Ying; Zhao, Julia Q; ... Yang, Wei (2017). Neuron-specific SUMO knockdown suppresses global gene expression response and worsens functional outcome after transient forebrain ischemia in mice. Neuroscience, 343. pp. 190-212. 10.1016/j.neuroscience.2016.11.036. Retrieved from https://hdl.handle.net/10161/23256.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Wulf Paschen

Professor in Anesthesiology
My research interests are understanding the mechanisms underlying induction of cell death induced by a severe form of cellular stress. I am particularly interested in the role of the endoplasmic reticulum in the pathological process induced by transient cerebral ischemia and culminating in neuronal cell death. This pathological process is associated with an irreversible suppression of protein synthese that limits the ability of cells to withstand ischemia-induced impairment of endoplasmic r
Sheng

Huaxin Sheng

Associate Professor in Anesthesiology
We have successfully developed various rodent models of brain and spinal cord injuries in our lab, such as focal cerebral ischemia, global cerebral ischemia, head trauma, subarachnoid hemorrhage, intracerebral hemorrhage, spinal cord ischemia and compression injury. We also established cardiac arrest and hemorrhagic shock models for studying multiple organ dysfunction.  Our current studies focus on two projects. One is to examine the efficacy of catalytic antioxidant in treating cerebral is
Warner

David Samuel Warner

Distinguished Distinguished Professor of Anesthesiology, in the School of Medicine
Humans may sustain a variety of forms of acute central nervous system injury including ischemia, trauma, vasospasm, and perinatal hypoxemia. The Multidisciplinary Neuroprotection Laboratories is dedicated to examining the pathophysiology of acute brain and spinal cord injury with particular reference to disease states managed in the perioperative or neurointensive care environments. Rodent recovery models of cerebral ischemia, traumatic brain injury, cardiopulmonary bypass, subarachnoid he
This author no longer has a Scholars@Duke profile, so the information shown here reflects their Duke status at the time this item was deposited.
Yang

Wei Yang

Associate Professor in Anesthesiology
Alphabetical list of authors with Scholars@Duke profiles.
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