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规范过程中发挥作用，对于中枢和周围神经系统中多个神经元谱系的发展至关重要。为了实现这些基本功能，bHLH因子的表达在空间和时间上都受到精确的调控。这种精确的控制确保了神经系统的发育，具有正确的神经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都是至关重要的。BHLH因子Ngn1、Ngn2和P48在神经管的增殖区表达，是脑和脊髓发育所必需的。这项建议的目标是利用这些特定的bHLH因子作为这一发育过程的模型调节器来确定控制神经发生和神经元规范的分子机制。此外，考虑到不同bHLH因子的区域特异性表达，它们将被用来绘制从胚胎神经管到成年大脑和脊髓的谱系。为了实现这些目标，我们将确定NGN1基因中控制时间和空间表达的不同调控序列，特别是在端脑背侧和背根神经节中。使用一种新的表达Ngn1-Cre的小鼠品系，我们将追踪从胚胎到出生阶段表达Ngn1的祖细胞的神经谱系，并测试这些谱系中对Ngn1的需求。我们将确定bHLH因子P48在背神经管中的功能，特别是关于其他bHLH因子的功能和调节。最后，我们将确定Ngn1在背侧和腹侧脊髓神经管中的相互作用因子，这些因子可能与Ngn1结合来控制神经元的规格。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。这些研究对理解多神经系统疾病的潜在生物学具有广泛的意义，并可能为未来治疗策略的理论基础提供洞察，特别是当它们与干细胞操作有关时。

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.