Regulation and Function of Mash1 in Neural Development

描述(申请人提供)：Mash1是一种必需的转录因子 在中枢和外周多个区域的神经发育中 神经系统。Mash1的表达受到严格的调控；它在 增殖的神经干细胞，随着细胞变得 有丝分裂后成熟为神经元。从多个数据集中综合结果 研究Mash1的表达和功能，我们假设(1)Mash1 表达受指示干细胞开始 分化程序，(2)特定bHLH功能的特异性 涉及相互作用的因素，以及(3)在神经前体细胞中，Mash1 在转录控制中的一些功能，但不是所有的途径所需的 神经元分化。这里的实验将解决这些假设，并且 确定其上游和下游的特定分子成分 必需的神经分化因子。我们将鉴定转录因子 结合Mash1增强子来控制脊髓神经中Mash1的表达 管子。我们将确定Mash1中的结构域，以满足特定需求 神经发生中的功能及相互作用因子的筛选 这些功能。最后，我们将确定具体的调控途径 Mash1基因调控的神经元分化过程 多种功能丧失和功能获得范例中的表达谱。 这项研究计划的成功将增加我们对分子的了解 神经前体增殖、分化和 规格。这一理解对未来的治疗很重要 神经细胞死亡相关神经性疾病的治疗策略 例如帕金森氏症，以及用于治疗的再生策略 脑部和脊髓受损。

DESCRIPTION (provided by applicant): Mash1 is an essential transcription factor in neural development throughout multiple regions of the central and peripheral nervous systems. Mash1 expression is tightly regulated; it is expressed in proliferating neural stem cells and is down-regulated as the cells become post-mitotic and mature into neurons. Synthesizing results from multiple investigators on Mash1 expression and function, we hypothesize that (1) Mash1 expression is controlled by signals instructing stem cells to begin the differentiation program, (2) the specificity of function for a particular bHLH involves interacting factors, and (3) in a neural progenitor cell, Mash1 functions in transcriptional control of some but not all pathways required for neuronal differentiation. Experiments here will address these hypotheses, and identify specific molecular components upstream and downstream of this essential neural differentiation factor. We will identify transcription factors that bind the Mash1 enhancer to control Mash1 expression in the spinal neural tube. We will identify structural domains in Mash1 required for specific functions in neurogenesis and screen for interacting factors that modulate these functions. And finally, we will identify the specific regulatory pathways during neuronal differentiation controlled by Mash1 by analysis of gene expression profiles in multiple loss- and gain-of-function paradigms. Success in this research program will increase our understanding of molecular mechanisms involved in neural precursor proliferation, differentiation, and specification. This understanding is important for future therapeutic strategies in treating neurological disorders involving neuronal cell death such as Parkinson's disease, and in regenerative strategies for treatment of brain and spinal cord damage.