bHLH Transcription Factors in Neural Development

描述（由申请人提供）：bHLH转录因子在神经发生和神经元特化过程中发挥作用，对于中枢和外周神经系统中多种神经元谱系的发育至关重要。为了实现这些基本功能，bHLH因子表达在空间和时间上都受到精确控制。这种精确的控制确保神经系统的发育具有正确的神经元细胞类型的组成和组织。因此，这些因子的调节和功能对于正常的神经发育至关重要。bHLH因子Ngn 1、Ngn 2和P48在神经管的增殖区中表达，并且是脑和脊髓发育所需的。这个建议的目标是定义控制神经发生和神经元规格的分子机制，使用这些特定的bHLH因子作为这个发育过程的模型调节器。此外，鉴于不同bHLH因子的区域特异性表达，它们将用于绘制从胚胎神经管到成人脑和脊髓的谱系。为了实现这些目标，我们将确定不同的调控序列ngnl基因控制时间和空间的表达，特别是在背侧端脑和背根神经节。使用一种新的Ngn 1-Cre表达小鼠品系，我们将追踪从胚胎到出生后阶段的Ngn 1表达祖细胞的神经谱系，并测试这些谱系中对Ngn 1的需求。我们将定义背神经管中bHLH因子P48的功能，特别是相对于其他bHLH因子的功能和调节。最后，我们将确定Ngn 1相互作用的因素，在背侧和腹侧脊髓神经管，可能会与Ngn 1控制神经元的规格。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。这些研究对理解多种神经系统疾病的潜在生物学具有广泛的意义，并可能为未来的治疗策略提供深入了解，特别是当它们与干细胞操作相关时。

DESCRIPTION (provided by applicant): bHLH transcription factors function during neurogenesis and neuronal specification, and are essential for the development of multiple neuronal lineages in the central and peripheral nervous systems. In order to fulfill these essential functions, bHLH factor expression is precisely controlled both spatially and temporally. This precise control ensures the development of a nervous system with the correct composition and organization of neuronal cell-types. Thus, both the regulation and function of these factors are critical for normal neural development. The bHLH factors Ngn1, Ngn2, and P48 are expressed in the proliferative zone of the neural tube and are required for brain and spinal cord development. The goal of this proposal is to define molecular mechanisms controlling neurogenesis and neuronal specification using these specific bHLH factors as model regulators of this developmental process. In addition, given the region specific expression of the different bHLH factors, they will be used to map lineages from the embryonic neural tube to the adult brain and spinal cord. To attain these goals, we will identify distinct regulatory sequences within the ngnl gene that control temporal and spatial expression particularly in the dorsal telencephalon and dorsal root ganglia. Using a novel Ngn1-Cre expressing mouse strain, we will trace the neural lineage of Ngn1-expressing progenitor cells from the embryo to postnatal stages, and test the requirement for Ngn1 in these lineages. We will define the functions of the bHLH factor P48 in dorsal neural tube particularly with respect to the function and regulation of the other bHLH factors present. And finally, we will identify Ngn1 interacting factors in the dorsal versus ventral spinal neural tube that may act in combination with Ngn1 to control neuronal specification. Success in this research program will increase our understanding of molecular mechanisms involved in neural precursor proliferation, differentiation, and specification. These studies have broad implications for understanding the underlying biology of multiple nervous system disorders, and may provide insight into future rationale for therapeutic strategies particularly as they relate to stem cell manipulation.