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受几种信号转导途径的控制，表明这些途径之间可能存在广泛的相互作用。然而，协调参与这一过程的不同信号级联反应的机制仍然不清楚。在这个提议中，我希望通过关注两个控制发育的重要信号之间的相互作用来解决这个重要问题;转录辅激活因子Yes相关蛋白（雅普），Hippo激酶级联的主要靶点，以及Sonic hedgehog（Shh）信号。该提案的主要目标是1）剖析雅普在脊髓发育中的功能，和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。该提议的总体假设是，雅普在控制NPC增殖和CNS中腹侧细胞命运的特化期间充当Shh的新型下游效应物。具体来说，我假设，YAP依赖的信号与Shh信号通路在多个层面上进行通信，提供了一种有效的手段，协调这两个转导级联在神经发育过程中。我将使用一系列分子方法、鸡胚和突变小鼠来检验这一假设。该提议的具体目的如下：1）确定雅普在神经管发育期间细胞类型特化中的作用和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中的发育。除了定义雅普和Shh信号协调正常CNS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.