Morphogen-dependent regulation of motor neurogenesis along the A/P axis

沿 A/P 轴运动神经发生的形态发生依赖调节

• 批准号: 8720824
• 负责人: Gary O Gaufo
• 金额: $ 31.83万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8720824
• 关键词: Address; Affect; Anterior; Brain; Cells; Central Nervous System Diseases; Childhood Medulloblastomas; Collagen; Cre-LoxP; Cues; Dependence; Development; Developmental Process; Dorsal; Dose; Embryo; Embryonic Development; Erinaceidae; Exposure to; Floor; Genes; Genetic; Germ-Line Mutation; Hereditary Disease; In Vitro; Knock-out; Location; Masks; Mediating; Modeling; Molecular; Motor; Motor Neurons; Mus; Neural tube; Neuraxis; Neurons; Pathway interactions; Pattern; Play; Production; Regulation; Repression; Role; Series; Signal Pathway; Signal Transduction; Sonic Hedgehog Pathway; Source; Spinal; Spinal Cord; Stem cells; System; Testing; Time; Transducers; base; brain cell; gain of function; hindbrain; in vivo; insight; morphogens; neurodevelopment; neurogenesis; notochord; progenitor; programs; repaired; research study; segregation; small hairpin RNA; smoothened signaling pathway; spatial temporal variation; tool; transcription factor

DESCRIPTION (provided by applicant): The coordination of spatial and temporal cues in the neural tube is essential for generating cell identity and diversity in the central nervous system (CNS). Here we test the role of the morphogen Sonic hedgehog (Shh) in coordinating these cues. In the vertebrate midline, secretion of Shh from the notochord is critical for inducing the floor plate in the overlying ventral neural tube, and subsequent production of Shh from this second signaling center. In a concentration and time dependent manner, Shh controls the identity and diversity of ventral neuronal subtypes along the dorsal-ventral (D/V) axis of the neural tube. Despite the large body of work that has established this mechanism, it is unknown how the hedgehog-patterning program is involved in generating cell identity and diversity along the anterior-posterior (A/P) axis. Using the developing hindbrain and the spinal cord as a model to represent the A/P axis, we explore this basic developmental question. We utilized genetic tools in the mouse to spatially and temporally dissect the function of the Shh pathway in both D/V and A/P axes. Our preliminary findings indicate that the hindbrain has a greater dependence and a longer requirement for floor plate-derived Shh compared to the spinal cord. This suggests that notochord-derived Shh plays a larger role in patterning the spinal cord than the hindbrain. Based on these findings, we test the hypothesis that spatial and temporal variations in the need for Shh result in the difference in cellular identity and diversity between the brain and the spinal cord. In aim 1 we will identify the combination of Shh transducers that mediate the difference in patterning between the hindbrain and the spinal cord. In aim 2 we ask how the early and late activities of hedgehog signaling in the notochord and the floor plate are coordinated to pattern the ventral neural tube. In aim 3 we will investigate how the Hox transcription factors, which provide positional information to progenitors along the A/P axis, and the Shh signaling pathway control cell diversity in the hindbrain from a common molecular ground state. Together, our studies will provide a conceptual framework for how different spatial and temporal cues are integrated at each level of the neural tube to generate the cellular profile that is unique for each division of the CNS.

描述（由申请人提供）：神经管中的空间和时间提示的协调对于产生中枢神经系统（CNS）的细胞身份和多样性至关重要。在这里，我们测试了形态学声音刺猬（SHH）在协调这些提示中的作用。在脊椎动物的中线中，从脊索中分泌SHH对于在上覆的腹侧神经管中诱导地板板以及随后从第二个信号中心产生SHH至关重要。 SHH以浓度和时间依赖的方式控制沿着神经管的背腹侧（D/V）轴的腹侧神经元亚型的身份和多样性。尽管已经建立了这种机制的大量工作，但尚不清楚刺猬造成的程序如何参与沿前后轴（A/P）轴产生细胞的身份和多样性。我们将发展的后脑和脊髓作为代表A/P轴的模型，我们探索了这个基本的发展问题。我们利用小鼠中的遗传工具在d/v和a/p轴上在空间和时间上剖析了SHH途径的功能。我们的初步发现表明，与脊髓相比，后脑脑对地板衍生的SHH具有更大的依赖性和更长的要求。这表明，诺修（Notochord）衍生的SHH在对脊髓构图中起着比后脑的作用更大的作用。基于这些发现，我们检验了以下假设：SHH需求的空间和时间变化会导致大脑和脊髓之间的细胞身份和多样性的差异。在AIM 1中，我们将确定介导后脑和脊髓之间图案差异的SHH传感器的组合。在AIM 2中，我们询问刺猬信号的早期和晚期活动是如何协调的，以对腹侧神经管进行配位。在AIM 3中，我们将研究HOX转录因子如何为沿A/P轴的祖细胞提供位置信息，以及SHH信号通路从公共分子基态中控制后脑的细胞多样性。总之，我们的研究将为如何在神经管的每个级别集成不同的空间和时间提示，以生成针对中枢神经系统每个分裂唯一的细胞谱的概念框架。