Grant: Discovery Grants Program - Individual

The bones, cartilage, muscles and tendons of the human body provide flexibility and movement to the individual. At the cellular level, the cytoskeleton performs an equivalent function, by orchestrating a variety of cellular shape changes and movements, including cell division, cell migration, cell outgrowth, and intracellular transport. But what regulates cytoskeleton dynamics and how is this change initiated? This research proposal is aimed at answering these questions. Specifically, we are focused at elucidating the genetic pathways and cellular mechanisms that allows the information contained in an external signal to be assimilated by the cell and relayed to the cytoskeleton to invoke cell shape changes. Our past research identified UNC-53 and the Navigators (NAVs), a family of proteins found in both worms and humans that regulate the migration of cells, the outgrowth of neuronal and cellular processes during development, and the ongoing transport of molecules in the cell during its lifetime. The subsequent characterization of novel molecular interactions and live imaging studies of cell migrations and outgrowth have suggested that NAVs exert their activity at the point of cytoskeleton assembly. But what instructs UNC-53/NAVs to do this?  There are two main thrusts of the research outlined in the current proposal: firstly, to identify the external signals and cell surface receptors that regulate UNC-53/NAV activity inside the cell; and, secondly, to understand the function of UNC-53/NAVs in intracellular transport. The Wnt family of signaling molecules are excellent candidate UNC-53 activators. Mutations in Wnt genes generate similar defects observed in unc-53 mutants. Using genetics, molecular biology and a variety of visual reporters as tools to highlight specific cell types, the current research is aimed at determining whether or not UNC-53 activity is dependent on Wnt signaling. As both the Navigators and Wnt signaling components are highly conserved in nature, the results obtained are likely to be generally relevant to our understanding of the molecular mechanisms behind some of the most basic physiological processes in a multi-cellular organism (e.g. how a nerve cell can grow out axons that extend long distances). Through this research program, several graduate and undergraduate students will receive advanced training in genetics, molecular biology, transgenesis, and high resolution microscopy techniques, preparing them for ongoing careers as researchers in academia or in the biotechnology industry.