title: Ischemic insults derepress the gene silencer REST in neurons destined to die.
abstract: A subset of genes implicated in genetic and acquired neurological disorders encode proteins essential to neural patterning and neurogenesis. The gene silencing transcription factor neuronal repressor element-1 silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF) plays a critical role in elaboration of the neuronal phenotype. In neural progenitor and non-neural cells, REST acts by repression of a subset of neural genes important to synaptic plasticity and synaptic remodeling, including the AMPA receptor (AMPAR) subunit GluR2. Here we show that global ischemia triggers REST mRNA and protein expression. REST suppresses GluR2 promoter activity and gene expression in neurons destined to die. Because the GluR2 subunit governs AMPAR Ca2+ permeability, these changes are expected to have profound effects on neuronal survival. In keeping with this concept, acute knockdown of the REST gene by antisense administration prevents GluR2 suppression and rescues post-ischemic neurons from ischemia-induced cell death in an in vitro model. To our knowledge, our study represents the first example of ischemia-induced induction of a master transcriptional regulator gene and its protein expression critical to neural differentiation and patterning in adult neurons. Derepression of REST is likely to be an important mechanism of insult-induced neuronal death.
authors.affiliation: Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Agata
authors.initials: A
authors.lastname: Calderone
authors.forename: Teresa
authors.initials: T
authors.lastname: Jover
authors.forename: Kyung-min
authors.initials: KM
authors.lastname: Noh
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Tanaka
authors.forename: Hidenori
authors.initials: H
authors.lastname: Yokota
authors.forename: Ying
authors.initials: Y
authors.lastname: Lin
authors.forename: Sonja Y
authors.initials: SY
authors.lastname: Grooms
authors.forename: Roodland
authors.initials: R
authors.lastname: Regis
authors.forename: Michael V L
authors.initials: MV
authors.lastname: Bennett
authors.forename: R Suzanne
authors.initials: RS
authors.lastname: Zukin
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D019194:Ischemic Preconditioning; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D018091:Receptors, AMPA; D012097:Repressor Proteins; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor; C104722:glutamate receptor ionotropic, AMPA 2