Regulation and Function of Ascl1 (Mash1) in Neural Development

描述（由申请人提供）：神经系统发育异常被认为是许多复杂神经系统疾病的基础。在过去的十年中，在几种脊椎动物中的研究表明，bHLH转录因子Ascl 1（以前称为Mash 1）对于神经元分化和亚型特化是必不可少的，用于在整个大脑，脊髓和自主神经系统以及神经内分泌和感觉细胞中产生多种神经元细胞类型。最近的研究表明，Ascl1也存在于注定成为少突胶质细胞的细胞中。该研究项目的重点是了解Ascl1在这些不同神经细胞类型产生中的调节和功能。首先，阐明调控Ascl 1水平的机制对于理解细胞数量控制是至关重要的，因为Ascl 1功能被置于循环祖细胞和有丝分裂后神经细胞之间的过渡的关键点。测试多个物种中保守序列重要性的实验将用于鉴定控制Ascl 1表达的调节机制。第二，Ascl1是已知的少数几个调节CNS多样性的转录因子之一，然而，因为Ascl1表达是短暂的，并且因为细胞在分化时可以经历广泛的迁移，所以很难识别成年大脑中Ascl1谱系中的细胞类型的完整补充。体内可诱导的遗传命运作图策略将用于鉴定脑中起源于Ascl1表达细胞的细胞类型的完整补体。最后，Ascl 1在少突胶质细胞发生中的功能将被检查，以比较其在神经发生中的功能。我们将确定和比较转录目标的Ascl1活性在空间和时间上不同的Ascl1表达组织，以揭示Ascl1功能的机制。这些实验将解决用于在CNS中产生正确数量和类型的神经元和少突胶质细胞的内在分子机制。相关性：由于Ascl 1在将细胞从祖细胞状态转变为分化状态中至关重要，因此Ascl 1的调节和功能的研究对于它们对公共卫生关注的多个领域的基本贡献具有重要意义，例如1）神经干细胞的操纵，2）神经系统的多种发育障碍（如自闭症和精神分裂症）中的基础生物学，和3）起源于神经组织的癌症，如胶质母细胞瘤和神经母细胞瘤。

DESCRIPTION (provided by applicant): Abnormal development of the nervous system is thought to underlie many complex neurological disorders. In the past decade, research in several vertebrate organisms has shown the bHLH transcription factor Ascl1 (previously Mash1) is essential for neuronal differentiation and sub-type specification for the generation of multiple neuronal cell-types throughout the brain, spinal cord, and autonomic nervous system, as well as neuroendocrine and sensory cells. Recent studies show that Ascl1 is also present in cells fated to become oligodendrocytes. The focus of this research project is to understand the regulation and function of Ascl1 in the generation of these diverse neural cell-types. First, elucidation of mechanisms regulating Ascl1 levels is critical for understanding cell number control since Ascl1 function is placed at a critical point in the transition between cycling progenitor cells and post-mitotic neural cells. Experiments testing the importance of sequences conserved across multiple species will be used to identify the regulatory mechanisms controlling Ascl1 expression. Second, Ascl1 is one of the few transcription factors known to regulate diversity in the CNS, however, because Ascl1 expression is transient, and because cells can undergo extensive migrations as they differentiate, it has been difficult to identify the full complement of cell-types in the adult brain that are in the Ascl1 lineage. An in vivo inducible genetic fate-mapping strategy will be used to identify the full complement of cell-types in the brain that have their origin in an Ascl1-expressing cell. And finally, the function of Ascl1 in oligodendrogenesis will be examined for comparison to its function in neurogenesis. We will identify and compare transcriptional targets of Ascl1 activity in spatially and temporally distinct Ascl1- expressing tissues to uncover the mechanism of Ascl1 function. These experiments will address intrinsic molecular mechanisms used to generate the correct number and type of neurons and oligodendrocytes in the CNS. Relevance: Since Ascl1 is critical in transitioning cells from a progenitor state to a differentiated state, studies of the regulation and function of Ascl1 hold significance for their fundamental contributions to multiple areas of concern to public health such as 1) manipulation of neural stem cells, 2) the underlying biology in multiple developmental disorders of the nervous system such as autism and schizophrenia, and 3) in cancers originating in neural tissue such as glioblastoma and neuroblastoma.