Regulation and Function of Ascl1 (Mash1) in Neural Development

Mashl是多个区域神经发育中的重要转录因子 中枢和外周神经系统的变化Mashl的表达受到严格的调控， 在增殖的神经干细胞中表达，并且随着细胞成为后 有丝分裂并成熟为神经元。综合来自Mashl上多个研究者的结果 表达和功能，我们假设1）Mashl表达受信号控制 指导干细胞开始分化程序，2）对细胞的功能特异性， 特定的bHLH涉及相互作用因子，和3）在神经祖细胞中，Mashl起作用 在神经元分化所需的一些但不是所有途径的转录控制中。 这里的实验将解决这些假设，并确定特定的分子成分 这个重要的神经分化因子的上游和下游。我们会确认的！ 结合Mash 1增强子以控制脊髓中Mash 1表达的转录因子 神经管我们将在Mashl中确定特定功能所需的结构域， 神经发生和筛选调节这些功能的相互作用因子。最后我们 将确定具体的：在神经元分化控制的调节途径， Mashl通过分析多个功能丧失和获得范例中的基因表达谱。 这项研究计划的成功将增加我们对分子机制的理解！ 参与神经前体增殖、分化和特化。这个啊！ 理解对于未来治疗神经系统疾病的治疗策略是重要的！ 涉及神经元细胞死亡，如帕金森氏病，并在再生策略， 治疗脑和脊髓损伤。J . J 3业绩地点（组织、城市、州） 德克萨斯大学西南医学中心，德克萨斯州达拉斯 关键人员。参见第11页的说明。根据需要使用续页，以下列格式提供所需信息。 名称组织在项目中的角色 放大图片作者：约翰逊. UT西南PI 亨克河迈克尔UT西南博士后 刘颖UT西南博士后 Zhao，Yingming UT西南合作者 PHS 398（Rev.4/98）第2 BB页 在整个应用程序的底部连续编号页面。不要使用后缀，如3a，3b。 CC首席研究员/项目主管（最后一位，第一位，中间一位）：Jfctne E.约翰逊 在各打印页和各续页的顶部键入主要研究者/项目负责人的姓名。(For型号规格，见 第6页的说明）。 研究资助 目录 页码 首页1 说明，

Mashl is an essential transcription factor in neural development throughout multiple regions of the central and peripheral nervous systems. Mashl expression is tightly regulated; it is expressed in proliferating neural stem cells and is downregulated as the cells become post- mitotic and mature into neurons. Synthesizing results from multiple investigators on Mashl expression and function, we hypothesize that 1) Mashl 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, Mashl 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 Mashl enhancer to control Mashl expression in the spinal neural tube. We will identify structural domains in Mashl 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 Mashl 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 fon treatment of brain and spinal cord damage. j . j 3ERFORMANCE SITE(S) (organization, city, state) University of Texas Southwestern Medical Center, Dallas, Texas KEY PERSONNEL. See instructions on Page 11. Usecontinuationpages as neededto provide the required information in the format shown below. Name Organization Role on Project Johnson, Jane E. UT Southwestern PI Henke, R. Michael UT Southwestern Postdoc Liu, Ying UT Southwestern Postdoc Zhao, Yingming UT Southwestern Collaborator PHS 398 (Rev.4/98) Page 2 BB Number pages consecutively at the bottom throughout the application. Do not use suffixes such as 3a, 3b. CC Princip^^estigator/Program Director (Last, first, middle): Jfctne E. Johnson Type the name of the principal investigator/program director at the top of each printed page and each continuation page. (For type specifications, see instructions on page 6.) RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description,