Math 1 in Neural Tube Development

描述（由申请人提供）：Math 1是一种bHLH转录因子，在神经发生和神经元特化过程中发挥作用，对多种神经元谱系的发育至关重要，包括小脑中的颗粒细胞、内耳中的感觉毛细胞和脊髓中的dl 1背连合中间神经元。为了实现这些基本功能，Math 1的表达在空间和时间上都受到精确控制，因为Math 1的错误表达会导致神经元的错误指定和死亡。因此，Math 1的调节和功能对于正常的神经发育至关重要。本提案的目标是使用Math 1作为模型调控基因来定义控制神经发生和神经元特异性的分子机制。为实现这一目标，将采取多种战略。首先，将确定Math 1表达的上游调节因子，其通过与Math 1增强子中的顺式调节序列相互作用发挥功能。这些调控基因可能是启动神经干/祖细胞分化的重要因素，并在背/腹轴的神经管图案。为了了解神经元分化和神经元特异性的分子基础，将使用基因组方法来鉴定Math 1转录活性的靶点。最后，为了了解神经bHLH因子引起的体内功能特异性，将鉴定与Math 1相互作用的蛋白质。这项研究计划的成功将增加我们对神经前体细胞增殖、分化和特化的分子机制的理解。这种理解对于未来使用神经干细胞治疗涉及疾病或创伤引起的神经元丢失的神经系统疾病非常重要。

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.