REST overexpression in mice causes deficits in spontaneous locomotion

Lü, Li; Marisetty, Anantha; Liu, Bin; Kamal, Mohamed M.; Gumin, Joy; Veo, Bethany; Cai, Yuanheng; Kassem, Dina H.; Weng, Connie C.; Maynard, Mark E.; Hood, Kimberly N.; Fuller, Gregory N.; Pan, Zhizhong Z.; Cykowski, Matthew D.; Dash, Pramod K.; Majumder, Sadhan

doi:10.1038/s41598-018-29441-3

Cited by 7 publications

(3 citation statements)

References 62 publications

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“…We then extracted mRNA from the tissues, picked 3 individual mRNA samples at random, and performed RNA sequencing. We analyzed the data as we described previously (Marisetty et al 2017; Lu et al 2018; Marisetty et al 2019).…”

Section: Resultsmentioning

confidence: 99%

Nerve injury inhibitsOprd1andCnr1transcription through REST in primary sensory neurons

Subedi,

Tiwari,

Etemad

et al. 2024

Preprint

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The transcription repressor REST in the dorsal root ganglion (DRG) is upregulated by peripheral nerve injury and promotes the development of chronic pain. However, the genes targeted by REST in neuropathic pain development remain unclear. The expression levels of 4 opioid receptor (Oprm1,Oprd1,Oprl1,Oprk1)and the cannabinoid CB1 receptor (Cnr1) genes in the DRG regulate nociception. In this study, we determined the role of REST in the control of their expression in the DRG induced by spared nerve injury (SNI) in both male and female mice. Transcriptomic analyses of male mouse DRGs showed that SNI upregulated expression ofRestand downregulated mRNA levels of all 4 opioid receptor andCnr1genes, butOprm1was upregulated in female mice. Analysis of publicly available bioinformatic data suggested that REST binds to the promoter regions ofOprm1andCnr1. Chromatin immunoprecipitation analyses indicated differing levels of REST at these promoters in male and female mice. Full-lengthRestconditional knockout in primary sensory neurons reduced SNI-induced pain hypersensitivity and rescued the SNI-induced reduction in the expression ofOprd1andCnr1in the DRG in both male and female mice. Our results suggest that nerve injury represses the transcription ofOprd1andCnr1via REST in primary sensory neurons and that REST is a potential therapeutic target for neuropathic pain.

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Section: Resultsmentioning

confidence: 99%

Nerve injury inhibitsOprd1andCnr1transcription through REST in primary sensory neurons

Subedi,

Tiwari,

Etemad

et al. 2024

Preprint

Self Cite

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show abstract

“…This mutant exon 4b does not introduce any stop codons and enables translation of the full-length product, albeit with some amino acid sequence differences (Nakano et al, 2018). Downregulation of REST is required, not only in HCs, but also in neurons (Mandel et al, 2011;Baldelli and Meldolesi, 2015;Lu et al, 2018). How is it, then, that a REST gain-of-function mutation leads to a cochlea-specific phenotype?…”

Section: Dfna27: Tissue-specific Requirements For Asmentioning

confidence: 99%

Alternative splicing in shaping the molecular landscape of the cochlea

Kim

Koo²,

Bok³

2023

Front. Cell Dev. Biol.

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The cochlea is a complex organ comprising diverse cell types with highly specialized morphology and function. Until now, the molecular underpinnings of its specializations have mostly been studied from a transcriptional perspective, but accumulating evidence points to post-transcriptional regulation as a major source of molecular diversity. Alternative splicing is one of the most prevalent and well-characterized post-transcriptional regulatory mechanisms. Many molecules important for hearing, such as cadherin 23 or harmonin, undergo alternative splicing to produce functionally distinct isoforms. Some isoforms are expressed specifically in the cochlea, while some show differential expression across the various cochlear cell types and anatomical regions. Clinical phenotypes that arise from mutations affecting specific splice variants testify to the functional relevance of these isoforms. All these clues point to an essential role for alternative splicing in shaping the unique molecular landscape of the cochlea. Although the regulatory mechanisms controlling alternative splicing in the cochlea are poorly characterized, there are animal models with defective splicing regulators that demonstrate the importance of RNA-binding proteins in maintaining cochlear function and cell survival. Recent technological breakthroughs offer exciting prospects for overcoming some of the long-standing hurdles that have complicated the analysis of alternative splicing in the cochlea. Efforts toward this end will help clarify how the remarkable diversity of the cochlear transcriptome is both established and maintained.

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“…REST may also play a pro-epileptic role through its repression of the dopamine receptor type 2 (DR2), with REST overexpression causing reduced transcript expression of the receptor (L. Lu et al 2018 ), and increased DR2 mRNA levels in the striatum of REST conditional knockout mice (Yu et al 2013 ). Dopamine is understood to be involved in epileptogenesis, with dopamine receptor types 1 and 2 having opposing roles.…”

Section: Effects Of Rest In Post Status-epilepticus Seizure Modelsmentioning

confidence: 99%

The functions of repressor element 1-silencing transcription factor in models of epileptogenesis and post-ischemia

Butler-Ryan

Wood

2021

Metab Brain Dis

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Epilepsy is a debilitating neurological disorder characterised by recurrent seizures for which 30% of patients are refractory to current treatments. The genetic and molecular aetiologies behind epilepsy are under investigation with the goal of developing new epilepsy medications. The transcriptional repressor REST (Repressor Element 1-Silencing Transcription factor) is a focus of interest as it is consistently upregulated in epilepsy patients and following brain insult in animal models of epilepsy and ischemia. This review analyses data from different epilepsy models and discusses the contribution of REST to epileptogenesis. We propose that in healthy brains REST acts in a protective manner to homeostatically downregulate increases in excitability, to protect against seizure through downregulation of BDNF (Brain-Derived Neurotrophic Factor) and its receptor, TrkB (Tropomyosin receptor kinase B). However, in epilepsy patients and post-seizure, REST may increase to a larger degree, which allows downregulation of the glutamate receptor subunit GluR2. This leads to AMPA glutamate receptors lacking GluR2 subunits, which have increased permeability to Ca2+, causing excitotoxicity, cell death and seizure. This concept highlights therapeutic potential of REST modulation through gene therapy in epilepsy patients.

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REST overexpression in mice causes deficits in spontaneous locomotion

Cited by 7 publications

References 62 publications

Nerve injury inhibitsOprd1andCnr1transcription through REST in primary sensory neurons

Nerve injury inhibitsOprd1andCnr1transcription through REST in primary sensory neurons

Alternative splicing in shaping the molecular landscape of the cochlea

The functions of repressor element 1-silencing transcription factor in models of epileptogenesis and post-ischemia

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