Nitric Oxide-Induced Neuronal to Glial Lineage Fate-Change Depends on NRSF/REST Function in Neural Progenitor Cells
Nitric Oxide-Induced Neuronal to Glial Lineage Fate-Change Depends on NRSF/REST Function in Neural Progenitor Cells
复制标题
DOI：
10.1002/stem.1749
复制
发表时间：
2014-09-01
期刊：
影响因子：
5.2
通讯作者：
Brundin, Lou
中科院分区：
文献类型：
--
作者：
Bergsland, Maria;Covacu, Ruxandra;Brundin, Lou
中枢神经系统组织的退化通常发生在神经炎症性疾病中，如多发性硬化症和神经创伤。在这种情况下，神经干细胞/祖细胞(NPC)群体被认为为退化区提供新的细胞。在正常大脑中，来自脑室下区的神经前体细胞产生的神经元定居在嗅球或纹状体中。然而，在神经炎症状态下，神经前体细胞向损伤部位迁移，形成少突胶质细胞和星形胶质细胞，而新形成的神经元则较少。因此，特定的NPC血统命运决定似乎对当地环境的信号做出了回应。炎症的指示信号依赖于过量的自由基一氧化氮(NO)，这是天然免疫反应的重要组成部分，因为NO在体外促进分化中的大鼠神经前体细胞向神经胶质细胞的命运转化。在这里，我们证明了NO诱导的神经元到胶质细胞命运的转换依赖于转录因子神经元限制性沉默因子-1(NRSF)/抑制因子-1沉默转录(REST)。一些神经元和神经胶质细胞系限制基因的染色质修饰状态在不暴露时发生了改变。这些变化与基因表达的变化不谋而合，表明了全球向神经胶质潜能的转变。有趣的是，通过阻断NRSF/REST的功能，染色质修饰的改变丢失，NO诱导的神经元到胶质细胞的开关被抑制。这表明NRSF/REST是鼻咽癌特异性天然免疫反应中的一个关键因素，并表明了一种来自炎症组织的信号促进神经胶质细胞形成的新机制。
Degeneration of central nervous system tissue commonly occurs during neuroinflammatory conditions, such as multiple sclerosis and neurotrauma. During such conditions, neural stem/progenitor cell (NPC) populations have been suggested to provide new cells to degenerated areas. In the normal brain, NPCs from the subventricular zone generate neurons that settle in the olfactory bulb or striatum. However, during neuroinflammatory conditions NPCs migrate toward the site of injury to form oligodendrocytes and astrocytes, whereas newly formed neurons are less abundant. Thus, the specific NPC lineage fate decisions appear to respond to signals from the local environment. The instructive signals from inflammation have been suggested to rely on excessive levels of the free radical nitric oxide (NO), which is an essential component of the innate immune response, as NO promotes neuronal to glial cell fate conversion of differentiating rat NPCs in vitro. Here, we demonstrate that the NO-induced neuronal to glial fate conversion is dependent on the transcription factor neuron-restrictive silencing factor-1 (NRSF)/repressor element-1 silencing transcription (REST). Chromatin modification status of a number of neuronal and glial lineage restricted genes was altered upon NO-exposure. These changes coincided with gene expression alterations, demonstrating a global shift toward glial potential. Interestingly, by blocking the function of NRSF/REST, alterations in chromatin modifications were lost and the NO-induced neuronal to glial switch was suppressed. This implicates NRSF/REST as a key factor in the NPC-specific response to innate immunity and suggests a novel mechanism by which signaling from inflamed tissue promotes the formation of glial cells.