Identification of Patched 1-interacting proteins involved in hedgehog signal transduction during vertebrate neural development

脊髓是中枢神经系统的一部分，它对各种感觉做出反应，如触摸、高温和疼痛，并协调使我们充满活力的运动。我的研究重点是胚胎中神经系统的模式事件，以及发育中的脊髓中的新生神经元如何通过某些蛋白质的作用变得专门化。这里概述的计划有可能引领脊髓研究的革命性工作。从广义上讲，脊髓由两种主要类型的专门神经元组成：运动神经元和中间神经元，前者负责调节运动，后者负责整合来自环境的感觉信息。它们一起形成一个网络，在胚胎发育期间以一种精确的方式连接起来。Sonic Hedheghog(或Shh)是神经系统中参与形成不同细胞类型的最重要的蛋白质之一。它是一种蛋白质，调节细胞之间的通讯，调节神经系统的发育。Shh活性的调节剂是一种名为Patched1(或ptch1)的蛋白质。当Shh将ptch1结合在细胞表面时，一系列鲜为人知的事件启动了促进运动神经元和中间神经元形成的遗传程序。因此，了解ptch1如何调节对Shh的反应将有助于揭示胚胎如何精确地产生巨大多样性的神经元。我已经在小鼠身上发现了一种新的ptch1突变，它会在发育过程中改变Shh的活性。我的目标是利用这个小鼠突变体来解开Shh活动在发育中的脊髓中是如何被调节的。通过将培养皿中的细胞改造成这种突变形式的ptch1，我已经确定了与ptch1相互作用的蛋白质。我提议的研究计划将研究这些与ptch1相互作用的蛋白质如何调节发育中的脊髓中的Shh功能。通过勾勒出调节Shh活性的蛋白质网络，我的研究将揭示不同类型的细胞，如运动神经元和中间神经元是如何形成并正确连接形成功能正常的脊髓的。

The spinal cord is the part of the central nervous system that responds to various sensations such as touch, heat and pain, and mediates the movement that animates us. My research focuses on the events that pattern the nervous system in the embryo and how newborn neurons in the developing spinal cord become specialized by the actions of certain proteins. The programme outlined here has the potential to lead revolutionary work in spinal cord research. Broadly speaking, the spinal cord consists of two major types of specialized neurons: motoneurons, which regulate movement, and interneurons, which integrate sensory information from the environment. Together, they form a network that is wired in a precise manner during the development of the embryo. One of the most important proteins involved in the formation of distinct cell types in the nervous system is Sonic Hedheghog (or Shh). It is a protein that mediates communication between cells to regulate the development of the nervous system. A regulator of Shh activity is a protein called Patched1 (or Ptch1). When Shh binds Ptch1 at the surface of a cell, a poorly understood series of events turns on a genetic programme that promotes the formation of motoneurons and interneurons. Understanding how Ptch1 regulates the response to Shh will therefore shed light on how the embryo generates the great diversity of neurons in a precise manner. I have identified a novel Ptch1 mutation in the mouse that alters Shh activity during development. My aim is to use this mouse mutant to unravel how Shh activity is regulated in the developing spinal cord. By engineering cells in a petri dish to make this mutant form Ptch1, I have identified proteins that interact with Ptch1. The research programme I am proposing will examine how these Ptch1-interacting proteins regulate Shh function in the developing spinal cord. By outlining the network of proteins that regulate the activity of Shh, my research will reveal how distinct cell types such as motoneurons and interneurons are made and correctly wired to form a functioning spinal cord.