The central nervous system consists of a highly organized array of neurons whose axons connect with one another in a precise fashion. We wish to understand how developing neurons extend from their place of birth along their stereotypic pathways to find their final target.
Both vertebrates and invertebrates face this same formidable task and it is clear that the solutions to this shared problem have been highly conserved. We are using molecular genetics to identify and characterise novel genes and gene products essential for neuronal guidance during development of the Drosophila CNS.
Molecules that direct neuronal growth
A principal focus of our research is a characterisation of the molecules that direct neuronal growth at the midline of the CNS. We have identified two molecules commissureless (comm) and roundabout (robo) that are essential for normal growth of neurons at the midline. Comm is a novel transmembrane molecule that is expressed at the midline and in commissural axons. Robo encodes a new member of the IgCAM superfamily that is expressed on longitudinal axons. Robo acts as a receptor for the midline derived axonal growth inhibitor, Slit.
We have demonstrated that Comm regulates Robo levels on axons and this is the primary mechanism used to direct axonal extension towards or away from the midline. This regulation occurs at the post-translational level. Comm inhibits Robo activity by preventing the protein reaching the axon surface. This is achieved by Comm harnessing the ubiquitination pathway to target Robo protein to an intracellular location. We are continuing to investigate how this process is regulated and how protein targeting is used by axons to dictate their outgrowth as they extend towards their targets.