Function of Olig2-Regulated Genes in Spinal Motor Neuron Development

中枢神经系统(CNS)神经回路的形成依赖于 未分化的干细胞和祖细胞在脑内产生不同类别的神经元和胶质细胞 刻板印象的态度。我们的主要目标是了解分子细节如何大体方面 细胞周期调节和分化与细胞命运的决定相协调。之前，我们确定了一个 由运动神经元(MN)选择性表达的bHLH类转录抑制因子Orig2 脊髓中的祖细胞，并参与协调MN发育的三个关键特征：MN- 特定的基因表达、细胞周期退出和一般神经元分化。由于寡核苷酸2的功能是 抑制者，我们假设Orig2必须通过其关闭MN表达的能力来指导MN的形成 其他控制干细胞命运、增殖和分化的重要调控基因 和中枢神经系统中的祖细胞。这些基因的身份目前尚不清楚。在体外和体内使用 鸡和小鼠脊髓基因功能的分析，我们将检测三个基因的调控表达 并确定这些基因如何控制MN分化的不同方面。 首先，我们将确定hes基因在控制神经bhlh蛋白表达中的作用。 Neurogenin2和MN祖细胞的总体分化能力。第二，我们将研究其角色 ID基因在抑制Orig2和Ngn2控制MN分化时机的功能中发挥作用。 第三，我们将测试PLZF的作用，这是一种控制其他组织中干细胞自我更新的转录因子， 维持脊髓祖细胞处于未分化状态。总而言之，这些研究将提供 对干细胞和祖细胞如何专门化以产生特定细胞类型的重大洞察 CNS，并提供对细胞分裂和分化过程的详细理解 都是受控制的。对这一过程的洞察对于我们理解不同类型的细胞如何在 神经系统是最初形成的，对当前和未来开发干细胞疗法的努力至关重要 修复受损或患病的神经组织。

The formation of neural circuits in the central nervous system (CNS) depends on the ability of undifferentiated stem and progenitor cells to produce distinct classes of neurons and glial cells in a stereotyped manner. Our main objective is to understand the molecular details of how general aspects of cell cycle regulation and differentiation are coordinated with cell fate decisions. Previously, we identified a bHLH class transcriptional represser called Olig2 that is selectively expressed by motor neuron (MN) progenitors in the spinal cord, and involved in coordinating three key features of MN development: MN- specific gene expression, cell cycle exit, and general neuronal differentiation. Since Olig2 functions as a represser, we hypothesize that Olig2 must direct MN formation through its ability to shut off the expression of other important regulatory genes that themselves control the fate, proliferation, and differentiation of stem and progenitor cells in the CNS. The identity of these genes is currently not known. Using in vitro and in vivo assays of gene function in chick and mouse spinal cord, we will examine the regulated expression of three newly identified Olig2 targets and determine how these genes control different aspects of MN differentiation. First, we will determine the role of Hes genes in controlling the expression of the proneural bHLH protein Neurogenin2 and the overall capacity of MN progenitors to differentiate. Second, we will examine the role that Id genes play in inhibiting the function of Olig2 and Ngn2 to control the timing of MN differentiation. Third, we will test the role of PLZF, a transcription factor that controls stem cell self-renewal in other tissues, in maintaining spinal cord progenitors in an undifferentiated state. Together, these studies will provide significant insight into how stem and progenitor cells become specialized to generate specific cell types in the CNS, and provide a detailed understanding of how the processes of cellular division and differentiation are controlled. Insights into this process are important for our understanding of how different cell types in the nervous system are initially formed, and critical for current and future efforts to develop stem cells therapies to repair injured or diseased neural tissue.