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

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只受几条信号转导途径的支配，这表明这些途径之间可能存在广泛的相互作用。然而，协调这一过程中涉及的不同信号级联的活动的机制仍然不明确。在这项提案中，我希望通过关注控制发育的两个重要信号之间的相互作用来解决这个重要问题：转录共激活因子Yes-Association Protein(YAP)和Sonic hedgehog(Shh)信号。YAP是河马激酶级联反应的主要靶标。这项建议的主要目标是1)剖析YAP在脊髓发育中的功能，以及2)确定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。这一提议的总体假设是，YAP在控制鼻咽癌增殖和指定中枢神经系统腹侧细胞命运的过程中，作为Shh的一个新的下游效应因子。具体地说，我假设YAP依赖的信号与Shh信号通路在多个水平上进行通信，为神经发育过程中协调这两个转导级联提供了有效的手段。我将使用一组分子方法、鸡胚胎和突变小鼠来验证这一假设。这项建议的具体目的如下：1)确定YAP在神经管发育过程中细胞类型指定中的作用；2)确定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。除了确定YAP和Shh信号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其他调节器官发生的信号网络的重要原则。

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.