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)中产生细胞特性和多样性是必不可少的。在这里，我们测试了形态发生因子Sonic Hedgehog(Shh)在协调这些线索中的作用。在脊椎动物的中线，脊索分泌Shh对于诱导上覆的腹侧神经管的底板，以及随后从这个第二信号中心产生Shh是至关重要的。Shh以浓度和时间依赖的方式控制沿神经管背侧-腹侧(D/V)轴的腹侧神经元亚型的同一性和多样性。尽管已经有大量的工作建立了这一机制，但刺猬图案化程序如何参与沿前后(A/P)轴产生细胞特性和多样性尚不清楚。我们以发育中的后脑和脊髓作为代表A/P轴的模型，探讨了这一基本的发育问题。我们利用小鼠的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。我们的初步发现表明，与脊髓相比，后脑对底板来源的Shh有更大的依赖性和更长的需求。这表明脊索来源的Shh在构建脊髓模式方面比后脑发挥更大的作用。基于这些发现，我们测试了这样一种假设，即Shh需求的空间和时间变化会导致大脑和脊髓之间细胞同一性和多样性的差异。在目标1中，我们将确定调节后脑和脊髓之间模式差异的Shh转导的组合。在目标2中，我们询问脊索和底板中的刺猬信号的早期和晚期活动是如何协调以形成腹侧神经管的。在目标3中，我们将研究沿A/P轴向祖细胞提供位置信息的HOX转录因子和Shh信号通路如何从共同的分子基态控制后脑的细胞多样性。总之，我们的研究将提供一个概念性的框架，说明不同的空间和时间线索如何在神经管的每个层面上整合，以产生对中枢神经系统的每个分裂都是唯一的细胞轮廓。

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.