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

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.