Math 1 in Neural Tube Development

神经管发育中的数学 1

• 批准号: 6807581
• 负责人: Jane E Johnson
• 金额: $ 36.08万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6807581
• 关键词: DNA binding protein; artificial chromosomes; binding sites; cell differentiation; chick embryo; chimeric proteins; developmental genetics; developmental neurobiology; gene deletion mutation; gene expression; genetic enhancer element; genetically modified animals; laboratory mouse; mutant; neural plate /tube; neurogenesis; neuroregulation; protein protein interaction; protein structure function; regulatory gene; reporter genes; transcription factor; yeast two hybrid system

DESCRIPTION (provided by applicant): Math1 is a bHLH transcription factor that functions during neurogenesis and neuronal specification, and is essential for the development of multiple neuronal lineages including granule cells in the cerebellum, sensory hair cells in the inner ear, and dl1 dorsal commissural interneurons in the spinal cord. In order to fulfill these essential functions, Math1 expression is precisely controlled both spatially and temporally, since mis-expression of Math1 leads to mis-specification of neurons and lethality. Thus, both the regulation and function of Math1 are critical for normal neural development. The goal of this proposal is to define molecular mechanisms controlling neurogenesis and neuronal specification using Math1 as a model regulatory gene. To attain this goal, multiple strategies will be pursued. First, upstream regulators of Math1 expression will be identified that function through interactions with cis-regulatory sequences in the Math1 enhancer. These regulatory genes may be important factors for initiating differentiation in neural stem/progenitor cells, and for patterning the neural tube in the dorsal/ventral axis. To understand the molecular rationale underlying neuronal differentiation and neuronal specification, genomic approaches will be used to identify targets of Math1 transcriptional activity. And finally, to understand the in vivo specificity of function elicited by the neural bHLH factors, proteins that interact with Math1 will be identified. 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 use of neural stem cells in treating neurological disorders involving loss of neurons from disease or trauma.

描述（由申请人提供）：Math1是一个BHLH转录因子，在神经发生和神经元规范过程中起作用，对于开发多个神经元谱系的发展至关重要，包括小脑中的颗粒细胞，内耳的感觉毛细胞，内耳中的感觉毛细胞以及脊髓固有的DL1背膜脑膜元。为了履行这些基本功能，MATH1表达在空间和时间上都得到了精确控制，因为Math1的错误表达导致神经元和致死性的错误指定。因此，Math1的调节和功能对于正常的神经发育至关重要。该建议的目的是定义使用MATH1作为模型调节基因控制神经发生和神经元规范的分子机制。为了实现这一目标，将采取多种策略。首先，将通过与Math1增强子中的顺式调节序列相互作用来识别Math1表达的上游调节剂。这些调节基因可能是启动神经茎/祖细胞分化的重要因素，以及在背轴/腹侧轴上模仿神经管。为了了解神经元分化和神经元规范的分子基本原理，将使用基因组方法来识别Math1转录活性的靶标。最后，要了解神经BHLH因子引起的功能的体内特异性，将确定与Math1相互作用的蛋白质。该研究计划的成功将增加我们对与神经前体增殖，分化和规范有关的分子机制的理解。这种理解对于将神经干细胞在治疗涉及疾病或创伤神经元丧失的神经系统疾病中的未来使用非常重要。