Neuron-specific SUMO knockdown suppresses global gene expression response and worsens functional outcome after transient forebrain ischemia in mice.
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 articleSubject
ProsencephalonNeurons
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/10161/23256Published Version (Please cite this version)
10.1016/j.neuroscience.2016.11.036Publication 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.
Collections
More Info
Show full item recordScholars@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
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
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.
Wei Yang
Associate Professor in Anesthesiology
Alphabetical list of authors with Scholars@Duke profiles.

Articles written by Duke faculty are made available through the campus open access policy. For more information see: Duke Open Access Policy
Rights for Collection: Scholarly Articles
Works are deposited here by their authors, and represent their research and opinions, not that of Duke University. Some materials and descriptions may include offensive content. More info