Calderone Agata, Jover Teresa, Noh Kyung-min, Tanaka Hidenobu, Yokota Hidenori, Lin Ying, Grooms Sonja Y, Regis Roodland, Bennett Michael V L, Zukin R Suzanne
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
J Neurosci. 2003 Mar 15;23(6):2112-21. doi: 10.1523/JNEUROSCI.23-06-02112.2003.
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.
一些与遗传性和获得性神经疾病相关的基因子集编码对神经模式形成和神经发生至关重要的蛋白质。基因沉默转录因子神经元抑制元件-1沉默转录因子（REST）/神经元限制性沉默因子（NRSF）在神经元表型的形成中起关键作用。在神经祖细胞和非神经细胞中，REST通过抑制对突触可塑性和突触重塑重要的一部分神经基因发挥作用，包括AMPA受体（AMPAR）亚基GluR2。在这里，我们表明全脑缺血会触发REST mRNA和蛋白质表达。REST抑制注定死亡的神经元中GluR2启动子活性和基因表达。由于GluR2亚基控制AMPAR的Ca2+通透性，这些变化预计会对神经元存活产生深远影响。与此概念一致，在体外模型中，通过反义给药急性敲低REST基因可防止GluR2抑制，并使缺血后神经元免受缺血诱导的细胞死亡。据我们所知，我们的研究代表了缺血诱导一个对成年神经元神经分化和模式形成至关重要的主转录调节基因及其蛋白质表达的首个实例。REST的去抑制可能是损伤诱导神经元死亡的重要机制。
