Regulation and Function of Ascl1 (Mash1) in Neural Development

Mashl是多个区域神经发育过程中必不可少的转录因子 中枢神经系统和外周神经系统。Mashl的表达受到严格的调控；它是 在增殖中的神经干细胞中表达，随着细胞的成熟而下调 有丝分裂并成熟为神经元。在Mashl上综合多个调查人员的结果 关于Mashl的表达和功能，我们假设1)Mashl的表达受信号控制 指示干细胞开始分化程序，2)功能的特异性 特定的bHLH涉及相互作用的因素，以及3)在神经前体细胞中，Mashl功能 转录调控神经元分化所需的某些途径，但不是所有途径。 这里的实验将解决这些假设，并确定特定的分子成分 这种重要的神经分化因子的上游和下游。我们会辨认的！ 结合Mashl增强子以控制脊髓中Mashl表达的转录因子 神经管。中的特定功能所需的Mashl中的结构域 神经发生和筛选调节这些功能的相互作用的因素。最后，我们 将确定特定的：神经元分化过程中的调控途径，由 Mashl通过分析多种功能丧失和功能获得范例中的基因表达谱。 这项研究的成功将增加我们对分子机制的了解！ 参与神经前体的增殖、分化和规范。这! 了解这一点对于未来治疗神经系统疾病的治疗策略非常重要！ 涉及神经细胞死亡，如帕金森氏病，并参与再生策略 脑和脊髓损伤的治疗。J 。J 3格式站点(S)(组织、市、州) 德克萨斯大学西南医学中心，达拉斯，德克萨斯州 关键人员。请参阅第11页的说明。根据需要使用第二页以如下所示的格式提供所需信息。 命名项目中的组织角色 约翰逊，简·E·UT西南派 亨克，R·迈克尔·德州西南大学博士后 刘英，西南大学博士后 赵英明，德州大学西南分校合作者 小灵通398(版本4/98)第2页BB 在整个应用程序的底部连续编号页码。不要使用3a、3b等后缀。 CC Princp研究员/项目总监(最后、第一、中间)：Jfctne E.Johnson 在每张打印页和每张续页的顶部输入首席调查员/项目主任的姓名。(有关类型规格，请参阅 第6页上的说明。) 研究补助金 目录 页码 正面第1页 描述，

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,