Grant: Discovery Grants Program - Individual

BACKGROUND: During the development of the nervous system, neurons migrate through complex environments to connect to their targets, ensuring that neural circuits are properly wired to function. After its initial assembly, the neuronal architecture that was laid out during embryogenesis needs to persist during subsequent development, in the face of the addition of neurons into the existing circuits and the physical stress exerted by growth and body movements. Whereas much research has identified key guidance cues and receptors that instruct migrating neurons, how the cellular responses to the cues are orchestrated in time and space during development is unclear. Similarly, it remains largely unexplored how the neuronal architecture that is established during embryogenesis is maintained during subsequent development. Our research aims to understand how the nervous system gets wired and how it is subsequently maintained ensuring continued connectivity and function. Using the powerful model organism C. elegans, we have identified novel and specific roles for heparan sulfate proteoglycans in modulating axon guidance signals during development. We have also identified a battery of “neuronal maintenance” mutants whose nervous systems initially develop normally but later become abnormally wired.MAIN OBJECTIVE: The goal of this project is to elucidate the molecular mechanisms underlying both (a) the guidance of migrations during the assembly of the nervous system, and (b) the long-term maintenance of neuronal architecture during subsequent growth and maturation. SPECIFIC OBJECTIVES: NSERC funding is requested for elucidating novel roles of heparan sulfate proteoglycans in axon guidance, and for identifying and studying novel neuronal maintenance molecules, in accordance with the following specific aims: 1. Elucidate the mechanism by which LON-2/glypican modulates netrin signals in axon guidance. 2. Study the separate role of a second glypican, GPN-1, in axon guidance. 3. Determine the role of two novel neuronal maintenance genes nema-1 and nema-2 that we have identified in our forward genetic screens for neuronal maintenance defective mutants. 4. Identify additional regulators of neuronal maintenance.CONCLUSION: This research program is an excellent opportunity for increasing our general understanding of nervous system development and the long-term maintenance of neuronal structure and function. Given the evolutionary conservation between C. elegans and vertebrates, we expect that our research will uncover general principles underlying the development and maintenance of neural circuits, and thus have significant and long-lasting impact on the fields of developmental neurobiology and neuroscience.