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

描述（由申请人提供）：神经管中空间和时间线索的协调对于在中枢神经系统（CNS）中产生细胞身份和多样性至关重要。在这里，我们测试的形态的刺猬（嘘）在协调这些线索的作用。在脊椎动物的中线，分泌的Shh从脊索是至关重要的诱导底板上覆腹神经管，并随后生产的Shh从这个第二个信号中心。Shh以浓度和时间依赖的方式控制腹侧神经元亚型的身份和多样性，沿着神经管的背-腹（D/V）轴。尽管已经有大量的工作建立了这种机制，但目前还不清楚刺猬图案程序是如何参与产生细胞特性和沿着前后（A/P）轴的多样性的。使用发育中的后脑和脊髓作为代表A/P轴的模型，我们探索这个基本的发展问题。我们在小鼠中利用遗传工具在空间和时间上剖析了Shh通路在D/V和A/P轴上的功能。我们的初步研究结果表明，后脑有一个更大的依赖性和更长的要求底板衍生的嘘相比，脊髓。这表明脊索来源的Shh在脊髓的模式化中比后脑起着更大的作用。基于这些发现，我们测试的假设，空间和时间的变化，需要嘘的结果在大脑和脊髓之间的细胞身份和多样性的差异。在目标1中，我们将确定介导后脑和脊髓之间模式差异的Shh换能器的组合。在目标2中，我们询问了脊索和底板中的刺猬信号的早期和晚期活动是如何协调的，以形成腹侧神经管的图案。在目标3中，我们将研究Hox转录因子如何从一个共同的分子基态控制后脑中的细胞多样性，Hox转录因子沿沿着A/P轴向祖细胞提供位置信息，Shh信号通路。总之，我们的研究将提供一个概念框架，不同的空间和时间的线索是如何整合在每个层次的神经管，以产生细胞的配置文件是唯一的每个部门的中枢神经系统。

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.