The Collaborative Roles of YAP and Sonic Hedgehog in the Developing Spinal Cord

YAP 和 Sonic Hedgehog 在脊髓发育中的协同作用

• 批准号: 8718304
• 负责人: Ashly Christine Leder
• 金额: $ 5.15万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-03 至 2017-04-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8718304
• 关键词: Activator Appliances; Address; Apoptosis; Binding; Cell Proliferation; Cells; Cellular Morphology; Chick Embryo; Complex; Coupled; Cyclic AMP-Dependent Protein Kinases; Cytoplasmic Granules; Data; Defect; Development; Developmental Process; Disinhibition; Erinaceidae; Goals; Growth; Holoprosencephaly; Injury; Mediating; Methods; Molecular; Mutant Strains Mice; Neural Tube Development; Neural tube; Neurodevelopmental Disorder; Neurons; Nuclear; Organ; Organ Size; Organogenesis; Pathway interactions; Pattern; Phosphotransferases; Play; Process; Proteins; Research; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Sonic hedgehog protein; Spinal Cord; Spinal Cord Diseases; Testing; Therapeutic; Transcription Coactivator; Work; base; cell fate specification; cell type; cofactor; design; human SMO protein; knock-down; medulloblastoma; nerve stem cell; neurodevelopment; novel; protein expression; protein function; public health relevance; receptor; smoothened signaling pathway; transcription factor

DESCRIPTION (provided by applicant): Complex developmental processes that define organ morphology and cellular differentiation appear to be governed by only several signal transduction pathways, suggesting the likelihood of extensive interactions among those pathways. However, the mechanisms that coordinate the activity of different signaling cascades involved in this process remain ill defined. In this proposal, I wish to tackle this important issu by focusing on the interplay between two prominent signals that control development; the transcription coactivator Yes- associated protein (YAP), the prime target of the Hippo kinase cascade, and Sonic hedgehog (Shh) signaling. The main goals of this proposal are to 1) dissect the function of YAP in spinal cord development, and 2) define how the Shh and Hippo signaling pathways act in concert to control development in the vertebrate spinal cord. The overall hypothesis of this proposal is that YAP serves as a novel downstream effector of Shh during the control of NPC proliferation and specification of ventral cell fates in the CNS. Specifically, I postulate that the YAP-dependent signaling communicates with the Shh signaling pathway at multiple levels, providing an effective means of coordinating these two transduction cascades during neural development. I will test this hypothesis using an ensemble of molecular methods, chick embryos and mutant mice. The specific aims of this proposal are as follows: 1) to determine the role of YAP in cell-type specification during neural tube development and 2) to define how the Shh and Hippo signaling pathways act in concert to control development in the vertebrate spinal cord. Besides defining the basic mechanisms by which YAP and Shh signaling coordinate key aspects of normal CNS development, this study should also uncover important principles applicable to other signaling networks that regulate organogenesis.

描述（由申请人提供）：定义器官形态和细胞分化的复杂发育过程似乎仅由几种信号转导途径控制，表明这些途径之间可能存在广泛的相互作用。然而，协调该过程中涉及的不同信号级联的活动的机制仍然不明确。在本提案中，我希望通过关注控制发展的两个重要信号之间的相互作用来解决这一重要问题；转录辅激活因子 Yes 相关蛋白 (YAP)、Hippo 激酶级联的主要靶标和 Sonic Hedgehog (Shh) 信号传导。该提案的主要目标是 1) 剖析 YAP 在脊髓发育中的功能，2) 定义 Shh 和 Hippo 信号通路如何协同作用来控制脊椎动物脊髓的发育。该提议的总体假设是，YAP 在控制 NPC 增殖和中枢神经系统腹侧细胞命运的规范过程中充当 Shh 的新型下游效应器。具体来说，我假设 YAP 依赖性信号在多个层面上与 Shh 信号通路进行通信，从而提供了在神经发育过程中协调这两个转导级联的有效方法。我将使用一系列分子方法、鸡胚胎和突变小鼠来检验这个假设。该提案的具体目标如下：1）确定 YAP 在神经管发育过程中细胞类型规范中的作用，2）定义 Shh 和 Hippo 信号通路如何协同作用来控制脊椎动物脊髓的发育。除了定义 YAP 和 Shh 信号传导协调正常中枢神经系统发育的关键方面的基本机制外，这项研究还应该揭示适用于调节器官发生的其他信号传导网络的重要原理。