Math 1 in Neural Tube Development

描述(申请人提供)：Math1是一种bHLH转录因子，在神经发生和神经元规范过程中发挥作用，对包括小脑颗粒细胞、内耳感觉毛细胞和脊髓DL1背侧连合中间神经元在内的多种神经元的发育至关重要。为了实现这些基本功能，Math1的表达在空间和时间上都受到精确的控制，因为Math1的错误表达会导致神经元的错误指定和致命性。因此，Math1的调节和功能对正常的神经发育都是至关重要的。这项建议的目标是以Math1作为模型调控基因来确定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，将采取多种战略。首先，Math1表达的上游调控因子将通过与Math1增强子中的顺式调控序列相互作用而发挥作用。这些调控基因可能是启动神经干细胞/祖细胞分化的重要因素，也可能是在背轴/腹轴上形成神经管的重要因素。为了了解神经元分化和神经元规范的分子基础，将使用基因组方法来识别Math1转录活性的靶标。最后，为了了解由神经bHLH因子引发的功能在体内的特异性，将识别与Math1相互作用的蛋白质。这一研究计划的成功将增加我们对神经前体增殖、分化和规范所涉及的分子机制的理解。这一认识对于未来使用神经干细胞治疗神经性疾病非常重要，这些疾病包括疾病或创伤造成的神经元丢失。

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.