BHLH TRANSCRIPTION FACTORS IN NEURAL DEVELOPMENT

描述(申请人摘要逐字复制)：四名 神经特异性bHLH转录因子家族、Ngn1、Ngn2、MASH1和 MATH1是哺乳动物神经系统发育所必需的。这些 因子在增殖的神经前体细胞中以精确的模式表达 在发育中的神经管内，它们的表达随着 细胞变成有丝分裂后并分化。从以前的研究中可以清楚地看到， MASH1和NGN1/2在脊髓神经中有不同的表达结构域 管子。然而，Ngn1和Ngn2有明显的重叠结构域，并且在 背神经管可能与MATH1重叠。目前还不清楚这些bhlh是否 因素是共表达的，或者每个因素是否标记了 重叠域。我们假设采用不同基因的神经前体 细胞命运需要bHLH因子的独特组合才能正确 区分和规范。另外，上游的因素， 调控这类bHLH的精确时间和空间表达 蛋白质可能控制神经干细胞向神经干细胞的转变 区分神经前体。为了解决这些假设， NGN1、NGG2、MATH1和MASH1在单个细胞水平的表达 发展中的脊髓神经管和各bHLH的功能要求 将确定在已识别神经元发育中的因素。这个 获得精确的时间和空间表达的机制 这些基因将被阐明，以增加对神经前体的理解 扩散性和规范性。这些实验将揭示出对 神经特异性bHLH因子在脊髓中的组织和作用 神经管，并进入控制神经发育的内在机制。

DESCRIPTION(Applicant's abstract reproduced verbatim): Four members of the neural specific bHLH family of transcription factors, NGN1, NGN2, MASH1 and MATH1, are essential for development of the mammalian nervous system. These factors are expressed in proliferating neural precursors in precise patterns within the developing neural tube, and their expression is extinguished as the cells become postmitotic and differentiate. From previous studies, it is clear that MASH1 and ngnl/2 have distinct expression domains within the spinal neural tube. However, ngnl and ngn2 have apparently overlapping domains, and in the dorsal neural tube these may overlap with MATH1. It is not clear if these bHLH factors are co-expressed or whether each marks a specific cell type within overlapping domains. We hypothesize that neural precursors that adopt distinct cell fates require a unique combination of bHLH factors for correct differentiation and specification. In addition, the upstream factors that regulate the precise temporal and spatial expression of this class of bHLH proteins may control the transition from a neural stem cell to a differentiating neural precursor. To address these hypotheses, the overlap of expression at a single cell level between ngnl, ngn2, MATH1, and MASH1 in the developing spinal neural tube, and the functional requirement for each bHLH factor in the development of identified neurons will be determined. The mechanisms functioning to obtain precise temporal and spatial expression of these genes will be elucidated to increase understanding into neural precursor proliferation and specification. These experiments will reveal insights into the organization and role of the neural specific bHLH factors in the spinal neural tube, and into the intrinsic mechanisms controlling neural development.