Transcriptional regulation of gene expression clusters in motor neurons following spinal cord injury

Spinal cord injury leads to severe problems involving impaired motor, sensory, and autonomic functions. After spinal injury there is an initial phase of hyporeflexia followed by hyperreflexia, often referred to as spasticity. Previous studies have suggested a relationship between the reappearance of endogenous plateau potentials in motor neurons and the development of spasticity after spinalization. To unravel the molecular mechanisms underlying the increased excitability of motor neurons and the return of plateau potentials below a spinal cord injury we investigated changes in gene expression in this cell population. We adopted a rat tail-spasticity model with a caudal spinal transection that causes a progressive development of spasticity from its onset after 2 to 3 wk until 2 mo postinjury. Gene expression changes of fluorescently identified tail motor neurons were studied 21 and 60 days postinjury. The motor neurons undergo substantial transcriptional regulation in response to injury. The patterns of differential expression show similarities at both time points, although there are 20% more differentially expressed genes 60 days compared with 21 days postinjury. The study identifies targets of regulation relating to both ion channels and receptors implicated in the endogenous expression of plateaux. The regulation of excitatory and inhibitory signal transduction indicates a shift in the balance toward increased excitability, where the glutamatergic N-methyl-d-aspartate receptor complex together with cholinergic system is up-regulated and the γ-aminobutyric acid type A receptor system is down-regulated. The genes of the pore-forming proteins Cav1.3 and Nav1.6 were not up-regulated, whereas genes of proteins such as nonpore-forming subunits and intracellular pathways known to modulate receptor and channel trafficking, kinetics, and conductivity showed marked regulation. On the basis of the identified changes in global gene expression in motor neurons, the present investigation opens up for new potential targets for treatment of motor dysfunction following spinal cord injury.

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Area-specific regulation of gene expression in monkey motor cortices during recovery from spinal-cord injury

Neuroscience Research ◽

10.1016/j.neures.2010.07.1234 ◽

2010 ◽

Vol 68 ◽

pp. e277

Author(s):

Akira Sato ◽

Noriyuki Higo ◽

Takao Oishi ◽

Yukio Nishimura ◽

Tatsuya Yamamoto ◽

...

Keyword(s):

Gene Expression ◽

Spinal Cord ◽

Spinal Cord Injury ◽

Regulation Of Gene Expression ◽

Cord Injury ◽

Specific Regulation

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RXRα Blocks Nerve Regeneration after Spinal Cord Injury by Targeting p66shc

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/8253742 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Pei Yu ◽

Kai Yang ◽

Min Jiang

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Nerve Regeneration ◽

Motor Neurons ◽

Regulation Of Gene Expression ◽

Hippocampal Neurogenesis ◽

Luciferase Assay ◽

Cord Injury

Nerve regeneration after spinal cord injury is regulated by many factors. Studies have found that the expression of retinoid X receptor α (RXRα) does not change significantly after spinal cord injury but that the distribution of RXRα in cells changes significantly. In undamaged tissues, RXRα is distributed in motor neurons and the cytoplasm of glial cells. RXRα migrates to the nucleus of surviving neurons after injury, indicating that RXRα is involved in the regulation of gene expression after spinal cord injury. p66shc is an important protein that regulates cell senescence and oxidative stress. It can induce the apoptosis and necrosis of many cell types, promoting body aging. The absence of p66shc enhances the resistance of cells to reactive oxygen species (ROS) and thus prolongs life. It has been found that p66shc deletion can promote hippocampal neurogenesis and play a neuroprotective role in mice with multiple sclerosis. To verify the function of RXRα after spinal cord injury, we established a rat T9 spinal cord transection model. After RXRα agonist or antagonist administration, we found that RXRα agonists inhibited nerve regeneration after spinal cord injury, while RXRα antagonists promoted the regeneration of injured neurites and the recovery of motor function in rats. The results showed that RXRα played an impeding role in repair after spinal cord injury. Immunofluorescence staining showed that p66shc expression was upregulated in neurons after spinal cord injury (in vivo and in vitro) and colocalized with RXRα. RXRα overexpression in cultured neurons promoted the expression of p66shc, while RXRα interference inhibited the expression of p66shc. Using a luciferase assay, we found that RXRα could bind to the promoter region of p66shc and regulate the expression of p66shc, thereby regulating nerve regeneration after spinal cord injury. The above results showed that RXRα inhibited nerve regeneration after spinal cord injury by promoting p66shc expression, and interference with RXRα or p66shc promoted functional recovery after spinal cord injury.

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1134: Gene Expression Profile Changes using CDNA Microarray Technology in Patients with Neurogenic Bladder Secondary to Spinal Cord Injury

The Journal of Urology ◽

10.1016/s0022-5347(18)35290-x ◽

2005 ◽

Vol 173 (4S) ◽

pp. 308-308

Author(s):

Jeffrey L. Evans ◽

Henry Lai ◽

Mustafa Ozen ◽

Bhuvaneswari Krishnan ◽

Michael Ittmann ◽

...

Keyword(s):

Gene Expression ◽

Spinal Cord ◽

Spinal Cord Injury ◽

Gene Expression Profile ◽

Neurogenic Bladder ◽

Cdna Microarray ◽

Expression Profile ◽

Microarray Technology ◽

Cord Injury ◽

Profile Changes

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233-LB: Spinal Cord Injury Inhibited-FGF21 Signaling Is Associated with Dysregulation of Metabolic Gene Expression in Mouse Liver and Adipose Tissue

Diabetes ◽

10.2337/db20-233-lb ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 233-LB

Author(s):

XIN-HUA LIU ◽

LAUREN HARLOW ◽

ZACHARY GRAHAM ◽

JOSHUA F. YARROW ◽

KENNETH CUSI ◽

...

Keyword(s):

Gene Expression ◽

Spinal Cord ◽

Spinal Cord Injury ◽

Adipose Tissue ◽

Mouse Liver ◽

Metabolic Gene ◽

Metabolic Gene Expression ◽

Cord Injury

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Restoration of breathing after opioid overdose and spinal cord injury using temporal interference stimulation

Communications Biology ◽

10.1038/s42003-020-01604-x ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Michael D. Sunshine ◽

Antonino M. Cassarà ◽

Esra Neufeld ◽

Nir Grossman ◽

Thomas H. Mareci ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Motor Neurons ◽

Drug Overdose ◽

Cervical Spinal Cord ◽

Opioid Overdose ◽

Electrode Position ◽

Spinal Motor Neurons ◽

Cord Injury ◽

Low Amplitude

AbstractRespiratory insufficiency is a leading cause of death due to drug overdose or neuromuscular disease. We hypothesized that a stimulation paradigm using temporal interference (TI) could restore breathing in such conditions. Following opioid overdose in rats, two high frequency (5000 Hz and 5001 Hz), low amplitude waveforms delivered via intramuscular wires in the neck immediately activated the diaphragm and restored ventilation in phase with waveform offset (1 Hz or 60 breaths/min). Following cervical spinal cord injury (SCI), TI stimulation via dorsally placed epidural electrodes uni- or bilaterally activated the diaphragm depending on current and electrode position. In silico modeling indicated that an interferential signal in the ventral spinal cord predicted the evoked response (left versus right diaphragm) and current-ratio-based steering. We conclude that TI stimulation can activate spinal motor neurons after SCI and prevent fatal apnea during drug overdose by restoring ventilation with minimally invasive electrodes.

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CD157 in bone marrow mesenchymal stem cells mediates mitochondrial production and transfer to improve neuronal apoptosis and functional recovery after spinal cord injury

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02305-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jing Li ◽

Heyangzi Li ◽

Simin Cai ◽

Shi Bai ◽

Huabo Cai ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Bone Marrow ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Motor Neurons ◽

Functional Recovery ◽

Mitochondrial Transfer ◽

Cord Injury ◽

Marrow Mesenchymal Stem Cells

Abstract Background Recent studies demonstrated that autologous mitochondria derived from bone marrow mesenchymal stem cells (BMSCs) might be valuable in the treatment of spinal cord injury (SCI). However, the mechanisms of mitochondrial transfer from BMSCs to injured neurons are not fully understood. Methods We modified BMSCs by CD157, a cell surface molecule as a potential regulator mitochondria transfer, then transplanted to SCI rats and co-cultured with OGD injured VSC4.1 motor neuron. We detected extracellular mitochondrial particles derived from BMSCs by transmission electron microscope and measured the CD157/cyclic ADP-ribose signaling pathway-related protein expression by immunohistochemistry and Western blotting assay. The CD157 ADPR-cyclase activity and Fluo-4 AM was used to detect the Ca2+ signal. All data were expressed as mean ± SEM. Statistical analysis was analyzed by GraphPad Prism 6 software. Unpaired t-test was used for the analysis of two groups. Multiple comparisons were evaluated by one-way ANOVA or two-way ANOVA. Results CD157 on BMSCs was upregulated when co-cultured with injured VSC4.1 motor neurons. Upregulation of CD157 on BMSCs could raise the transfer extracellular mitochondria particles to VSC4.1 motor neurons, gradually regenerate the axon of VSC4.1 motor neuron and reduce the cell apoptosis. Transplantation of CD157-modified BMSCs at the injured sites could significantly improve the functional recovery, axon regeneration, and neuron apoptosis in SCI rats. The level of Ca2+ in CD157-modified BMSCs dramatically increased when objected to high concentration cADPR, ATP content, and MMP of BMSCs also increased. Conclusion The present results suggested that CD157 can regulate the production and transfer of BMSC-derived extracellular mitochondrial particles, enriching the mechanism of the extracellular mitochondrial transfer in BMSCs transplantation and providing a novel strategy to improve the stem cell treatment on SCI.

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