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仅由几种信号转导途径控制，这表明这些途径之间可能存在广泛的相互作用。然而，协调参与这一过程的不同信号级联活动的机制仍然不明确。在这一建议中，我希望通过关注控制发展的两个突出信号之间的相互作用来解决这一重要问题；转录辅助激活因子Yes- associated protein (YAP)， Hippo激酶级联的主要靶标，以及Sonic hedgehog （Shh）信号。本提案的主要目标是：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以控制脊椎动物脊髓的发育。该建议的总体假设是YAP在控制鼻咽癌增殖和中枢神经系统腹侧细胞命运的过程中作为Shh的一种新的下游效应物。具体来说，我假设yap依赖的信号在多个层面上与Shh信号通路进行交流，在神经发育过程中提供了一种有效的协调这两个转导级联的手段。我将用一系列分子方法，鸡胚胎和变异老鼠来验证这个假设。本提案的具体目的如下：1)确定YAP在神经管发育过程中细胞类型规范中的作用；2)确定Shh和Hippo信号通路如何协同作用以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关键方面的基本机制外，本研究还应揭示适用于调节器官发生的其他信号网络的重要原理。

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.