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，对各种感觉做出反应，如触摸，热和疼痛，并调节使我们充满活力的运动。我的研究重点是胚胎中神经系统模式的事件，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而变得专业化。这里概述的计划有可能导致脊髓研究的革命性工作。一般来说，脊髓由两种主要类型的特化神经元组成：运动神经元，其调节运动，以及中间神经元，其整合来自环境的感觉信息。它们共同形成一个网络，在胚胎发育过程中以精确的方式连接。参与神经系统中不同细胞类型形成的最重要蛋白质之一是Sonic Hedheghog（或Shh）。它是一种蛋白质，介导细胞之间的通信，以调节神经系统的发育。Shh活性的调节因子是一种称为Patched1（或Ptch1）的蛋白质。 当Shh与细胞表面的Ptch 1结合时，一系列知之甚少的事件开启了一个促进运动神经元和中间神经元形成的遗传程序。因此，了解Ptch 1如何调节对Shh的反应将有助于了解胚胎如何以精确的方式产生多种多样的神经元。我在小鼠中发现了一种新的Ptch1突变，它在发育过程中改变了Shh的活性。我的目标是利用这种小鼠突变体来阐明Shh活性在发育中的脊髓中是如何调节的。通过在培养皿中对细胞进行工程改造，使其形成Ptch 1的突变体，我已经鉴定出与Ptch 1相互作用的蛋白质。我提出的研究计划将研究这些Ptch1相互作用蛋白如何调节发育中脊髓的Shh功能。通过概述调节Shh活性的蛋白质网络，我的研究将揭示运动神经元和中间神经元等不同细胞类型是如何形成并正确连接以形成功能性脊髓的。

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.