IBN-9604504 PI: SEEGER One of the great challenges of modern neurobiology is to explain how complex nervous systems with millions of specialized connections are properly "wired" during development. We now appreciate that neuronal growth cones utilize a variety of cues to navigate along stereotypical pathways as they extend and locate their specific synaptic targets. These cues are diverse and can influence growth cones through either attractive or inhibitory mechanisms and can function as short-range, contact mediated factors or as long-range, diffusible signals. Although this basic framework for growth cone guidance is well established, our understanding of how any of these different signals actually work is at best quite limited. In particular, little is known about the actual mechanisms of chemotropic axon guidance. Dr. Seeger proposes to investigate the function of two chemotropic guidance molecules, called Netrins, during the development of the Drosophila (fruit fly) central nervous system. Netrins are an evolutionarily conserved family of chemotropic guidance molecules. Vertebrate Netrins play an important role in the attraction of commissural growth cones to the floor plate in the developing spinal cord. UNC-6, the first member of this protein family, is required for the normal circumferential migration of axons and other cells in the nematode, C. elegans. The identification of Netrins in Drosophila provides an excellent opportunity for a detailed molecular genetic dissection of this chemotropic guidance pathway by capitalizing on the many advantages that Drosophila offers as a model developmental genetic system. Results from the experiments outlined in this proposal will provide insights into the molecular mechanisms by which these chemotropic signals influence neuronal growth cones.
