Regulation of glial lineage by Olig2

Olig2 对神经胶质谱系的调节

• 批准号: 8063284
• 负责人: Akiko Nishiyama
• 金额: $ 18.24万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8063284
• 关键词: Active Sites; Antigens; Astrocytes; BHLH Protein; Bacterial Artificial Chromosomes; Biological Assay; Brain; CSPG4 gene; Cells; DNA Methylation; Development; Dorsal; Down-Regulation; Embryo; Epigenetic Process; Future; Genes; Genetic Transcription; Glial Differentiation; Glial Fibrillary Acidic Protein; Gray unit of radiation dose; Histone Code; In Vitro; Injury; Knock-out; Lead; Lesion; Luciferases; Maps; Medical center; Microglia; Modification; Mus; Myelin; Myelin Basic Proteins; NG2 antigen; Neocortex; Neuraxis; Neuroglia; Oligodendroglia; Pathway interactions; Play; Population; Prosencephalon; Proteins; Proteolipids; Protoplasmic Astrocyte; Regulation; Reporter; Rest; Role; Screening procedure; Serum; Signal Pathway; Signal Transduction; Staging; Tamoxifen; Techniques; Testing; Texas; Transgenic Mice; Transgenic Organisms; Universities; cell type; gray matter; human PDGFA protein; in vivo; injury and repair; neocortical; nerve stem cell; oligodendrocyte lineage; oligodendrocyte precursor; postnatal; precursor cell; prevent; progenitor; promoter; public health relevance; recombinase; repaired; research study; small molecule libraries; subventricular zone; transcription factor; white matter

DESCRIPTION (provided by applicant): Glial cells in the mammalian central nervous system (CNS) that express the NG2 proteoglycan (NG2 cells) appear during late embryonic stages and rapidly expand to uniformly occupy the entire CNS. These cells are distinct from mature oligodendrocytes, astrocytes, or resting ramified microglia and represent a fourth major glial population. Cultured NG2 cells give rise to oligodendrocytes and are thus called oligodendrocyte precursor cells (OPCs). In vivo fate mapping studies using our newly generated NG2creBAC transgenic mice revealed that NG2 cells in the white matter and dorsal forebrain generate exclusively oligodendrocytes, while those in the gray matter of the ventral forebrain generate both oligodendrocytes and protoplasmic astrocytes. When the basic helix-loop-helix transcription factor Olig2 is deleted in NG2 cells, almost all the NG2 cells in the dorsal forebrain differentiate into astrocytes at the expense of oligodendrocytes, resulting in myelin loss. Thus, NG2 cells retain lineage plasticity, and a single transcription factor Olig2 plays a critical role in maintaining the oligodendroglial fate of NG2 cells. Deletion of Olig2 in more differentiated oligodendrocytes does not alter the level of neocortical GFAP expression, in contrast to Olig2 deletion at earlier stages, suggesting that there is a developmental window in which oligodendrocyte lineage cells can be converted into astrocytes in the absence of Olig2. Aim 1 will test the hypothesis that NG2 cells lose their lineage plasticity and become incapable of generating astrocytes as they mature into oligodendrocytes, and that restriction of lineage plasticity in NG2 cells is regulated by epigenetic mechanisms. Aim 2 will test the hypothesis that there is a signaling pathway that maintains the expression of Olig2 in NG2 cells in the normal brain and prevents them from differentiating into astrocytes. This will be explored by screening small-molecule libraries for a compound that alters Olig2 transcriptional activity. Identified compounds will be used in future studies to delineate the endogenous signaling pathways that regulate Olig2 expression. The pathway could then be manipulated in future injury repair paradigms to promote differentiation of NG2 cells into the desired cell type. PUBLIC HEALTH RELEVANCE: NG2 cells represent a glial progenitor population that is ubiquitously distributed throughout the gray and white matter of the central nervous system. The proposed studies are aimed to identify the mechanisms that regulate their lineage plasticity through the transcription factor Olig2. The results from these studies can be used in future experiments in which the fate of endogenous NG2 cells can be manipulated to maximize their contribution to lesion repair in various types injury.

描述（由申请人提供）：表达NG2蛋白聚糖的哺乳动物中枢神经系统（CNS）中的神经胶质细胞（NG2细胞）出现在胚胎晚期，并迅速扩张以均匀地占据整个CNS。这些细胞与成熟的少突胶质细胞、星形胶质细胞或静息分枝小胶质细胞不同，代表第四种主要胶质细胞群。培养的 NG2 细胞产生少突胶质细胞，因此被称为少突胶质细胞前体细胞 (OPC)。使用我们新生成的 NG2creBAC 转基因小鼠进行的体内命运图谱研究表明，白质和背侧前脑中的 NG2 细胞仅生成少突胶质细胞，而腹侧前脑灰质中的 NG2 细胞同时生成少突胶质细胞和原生质星形胶质细胞。当NG2细胞中的碱性螺旋-环-螺旋转录因子Olig2被删除时，背侧前脑中几乎所有的NG2细胞都会以少突胶质细胞为代价分化为星形胶质细胞，导致髓鞘质损失。因此，NG2细胞保留了谱系可塑性，并且单个转录因子Olig2在维持NG2细胞的少突胶质细胞命运中发挥着关键作用。与早期阶段的 Olig2 缺失相比，分化程度更高的少突胶质细胞中 Olig2 的缺失不会改变新皮质 GFAP 表达水平，这表明存在一个发育窗口，在该窗口中，少突胶质细胞谱系细胞可以在缺乏 Olig2 的情况下转化为星形胶质细胞。目标 1 将检验以下假设：NG2 细胞在成熟为少突胶质细胞时失去其谱系可塑性并且无法生成星形胶质细胞，并且 NG2 细胞中谱系可塑性的限制受到表观遗传机制的调节。目标 2 将检验以下假设：存在一条信号通路维持正常大脑 NG2 细胞中 Olig2 的表达并阻止它们分化为星形胶质细胞。这将通过筛选小分子文库中改变 Olig2 转录活性的化合物来探索。已鉴定的化合物将用于未来的研究，以描绘调节 Olig2 表达的内源信号通路。然后可以在未来的损伤修复范例中操纵该途径，以促进 NG2 细胞分化为所需的细胞类型。 公共卫生相关性：NG2 细胞代表神经胶质祖细胞群，普遍分布在中枢神经系统的灰质和白质中。拟议的研究旨在确定通过转录因子 Olig2 调节其谱系可塑性的机制。这些研究的结果可用于未来的实验，在这些实验中，可以操纵内源性 NG2 细胞的命运，以最大限度地发挥它们对各种类型损伤中病变修复的贡献。