Grant: Discovery Grants Program - Individual

Model organisms like the fruit fly are widely used to study conserved developmental signalling pathways. The Wnt signalling cascade is critical for proper nervous system development. Although proteins involved in Wnt signalling are expressed in the adult nervous system of invertebrates and vertebrates, their function in long-term neuronal homeostasis remains unclear. In addition, the molecular mechanisms that regulate Wnt pathways are context-dependent (cell type, timing). There is growing evidence that genes involved in Wnt signalling and regulation (Wnt-related genes) are important for long-term neuronal function, but due to the critical role of Wnt in development, most mutant animals (across species) for these Wnt-related genes do not survive to adulthood, posing an experimental challenge. To overcome this hurdle and systematically determine the role of Wnt-related genes in the adult nervous system, we will use state-of-the-art genetic technologies in fruit flies. We will alter (increase or decrease) Wnt-related gene expression specifically in adult fly neurons or glia and determine how these changes in Wnt affect lifespan, neuronal function, and functional output of the organism. This strategy proved useful when I recently identified the fly protein Pits as a novel negative regulator of Wnt in neurons. Adult-specific loss of Pits in neurons leads to decreased lifespan as well as age-dependent motor deficits, as well as neuronal and axonal loss. However, it is still unclear exactly how Pits mediates Wnt repression. In the long-term, this research program will determine the role of these genes in specific neuronal or glial sub-types, the molecular mechanism underlying canonical and noncanonical Wnt pathways in the brain and examine other essential developmental pathways that are a challenge to study in the mature nervous system due to their role in development. In the short term we will: 1)Dissect the mechanistic role of Pits in Wnt repression. 2)Determine if known Wnt-related genes are important for long-term neuronal homeostasis and function. 3)Determine how Wnt maintains long-term neuronal homeostasis. My work will also generate genetic tools in flies that will be deposited in stock centers for the global fly community. My work will benefit the neuroscience community and advance our understanding of conserved mechanisms of long-term neuronal homeostasis and function. This research program will involve screening pipelines and hypothesis-driven objectives that will be highly conducive to multiple projects in the lab. These projects will vary in scale for highly qualified personnel (HQP) of all levels, from transient undergraduates to long-term trainees.