Project 453295

This proposal focuses on the role of Sonic hedgehog (Shh) and Netrin-1 in the formation of the nervous system. In particular, we are interested in how Shh and Netrin-1 help direct neurons such that they form the proper connections during nervous system development. To correctly form neuronal circuits, developing neurons send out a long extension, the axon, which moves through the embryo to find its target. Gradients of attractive and repulsive molecular cues act on axons to guide them to their appropriate targets. Both Shh and Netrin-1 can direct the movement of axons. They attract axons from spinal cord neurons, but how they do this is not well understood. Thus, our general objective is to understand at the molecular level how Shh and Netrin-1 regulate the guidance of axons. To guide axons, Shh and Netrin-1 induce physical changes in the growth cone, a motile structure at the growing tip of an axon. We will study how Shh and Netrin-1 regulate changes in the growth cone, specifically the growth cone cytoskeleton, which is a dynamic structure in the growth cone that underlies growth cone movement and turning. On the growth cone, Shh binds to its receptor Boc and Netrin-1 binds to its receptor DCC to guide axons. But how Boc and DCC communicate with the cytoskeleton to induce cytoskeletal remodelling is poorly understood. We have identified proteins that interact with Boc and DCC, and which may also regulate cytoskeleton remodelling. We will test whether these proteins are required for Shh and Netrin-1 to guide spinal cord axons. Since Shh and Netrin-1 collaborate to guide axons, these proteins may also be involved in coordinating the effect of Shh and Netrin-1 at the growth cone. Elucidating the molecular mechanisms of neural circuitry formation will help to better understand neurodevelopmental diseases involving axon guidance defects, such as mirror movements.