Program in Molecular and Cellular Pharmacology, State University of New York at Stony Brook, Stony Brook, New York 11794, USA.
J Neurosci. 2011 Mar 2;31(9):3470-83. doi: 10.1523/JNEUROSCI.2768-10.2011.
The RE1-silencing transcription factor (REST) represses the expression of neuronal-specific genes in non-neuronal cells by recruiting histone deacetylases (HDACs) and other histone modifying and chromatin remodeling proteins to the DNA. REST regulation of the expression of neuronal genes is required for the orderly developmental transition from a neuroepithelial stem cell to a functional neuron. Here, we examined the expression and function of REST in neonatal rat oligodendrocyte precursor cells (OPCs). OPCs develop from the same neuroepithelial stem cells as neurons, can be reprogrammed to act as neural stem-like cells in vitro, and require HDAC-mediated gene repression to develop into mature oligodendrocytes. We show that OPCs express functional REST protein and that REST interacts with several neuronal-specific genes whose expression is repressed in OPCs. REST transcript and protein expression increased fourfold during the first 48 h of oligodendrocyte differentiation. During this differentiation, the expression of RE1 containing neuronal genes further decreased as the transcription of oligodendrocyte-specific genes was activated. Expression of a dominant-negative form of REST in OPCs prevented the cells from developing into mature MBP-positive oligodendrocytes. Rather, the cells began to develop a neuronal phenotype characterized by increased expression of neuronal proteins, transcription factors, and cell-type-specific marker antigens. REST overexpression promoted the development of O4-positive pre-oligodendrocytes from OPCs. Together, these results show that REST function is required for the differentiation of OPCs into oligodendrocytes. By regulating the expression of neuronal genes, REST may also regulate the phenotypic plasticity of OPCs.
RE1 沉默转录因子 (REST) 通过招募组蛋白去乙酰化酶 (HDAC) 和其他组蛋白修饰和染色质重塑蛋白到 DNA 上来抑制非神经元细胞中神经元特异性基因的表达。REST 对神经元基因表达的调节是神经上皮干细胞向功能性神经元有序发育转变所必需的。在这里，我们研究了 REST 在新生大鼠少突胶质前体细胞 (OPC) 中的表达和功能。OPC 起源于与神经元相同的神经上皮干细胞，可以在体外被重新编程为神经干细胞样细胞，并且需要 HDAC 介导的基因抑制才能发育成成熟的少突胶质细胞。我们表明 OPC 表达功能性 REST 蛋白，REST 与几个神经元特异性基因相互作用，这些基因在 OPC 中被抑制表达。在少突胶质分化的前 48 小时内，REST 转录本和蛋白表达增加了四倍。在此分化过程中，随着少突胶质细胞特异性基因的转录被激活，含有 RE1 的神经元基因的表达进一步降低。在 OPC 中表达显性负形式的 REST 可阻止细胞分化为成熟的 MBP 阳性少突胶质细胞。相反，细胞开始表现出神经元表型，其特征是神经元蛋白、转录因子和细胞类型特异性标记抗原的表达增加。REST 过表达促进了 OPC 向 O4 阳性前少突胶质细胞的分化。总之，这些结果表明 REST 功能对于 OPC 分化为少突胶质细胞是必需的。通过调节神经元基因的表达，REST 还可能调节 OPC 的表型可塑性。
