Optogenetic Control of Notch Signalling in vivo

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Our bodies are made up of trillions of tiny cells that are stuck together to make organs and tissues. To ensure that each cell maintains its unique identity, it is wrapped up in an outer sheet or 'plasma membrane' that compartmentalizes its contents. However, the cells in our bodies also need to communicate with one another in order to coordinate their function during development and homeostasis. The central theme of our research program is the Notch singling pathway. The Notch pathway is a cell-to-cell communication system used by multi-cellular animals to ensure the correct cell types form at a precise time and location in the body. Remarkably, this system is used over and over again during the formation of almost every cell type. Given the extensive requirement for Notch, it is not surprising that defects in this signaling pathway are associated with many human developmental diseases and cancers.***In recent years, our understanding of the mechanisms that govern Notch signaling has grown significantly and provided insights into the cellular and genetic requirements for Notch. In particular, endocytic trafficking, the process by which cells internalize, sort, integrate, process, and secrete intercellular signaling components, has emerged as a critical regulator of Notch signaling. However, the complex, interconnected architecture of cellular signaling networks has posed formidable challenges to disentangling how cells process and integrate information. To circumvent these challenges, we apply a combination of genetic engineering, high resolution live imaging, and Optogenetics to precisely visualize and control components of the Notch pathway and the endocytic trafficking machinery with light. ***We use the fruit fly (Drosophila) and human cells as model systems for investigating the relationship between the signaling and trafficking machineries owing to the availability of sophisticated genetic tools, the high degree of conservation in the genes involved in Notch signaling and endocytic trafficking between flies and humans, and the ease with which students can gain the expertise required to perform sophisticated Optogenetic experiments. This approach will allow us to study the role of Notch signaling and endocytic trafficking in establishing boundaries between neighbouring tissues, in regulating stem cell differentiation, and will significantly advance our understanding of the mechanisms that control the Notch pathway and the endocytic trafficking machinery. We anticipate that our research program will generate both information-rich data sets and excellent opportunities for collaboration, will serve as an immersive training platform for undergraduate, graduate, and postgraduate students, and will provide fundamental mechanistic insights and novel hypotheses into the regulatory architecture of Notch signaling and endocytic trafficking during multicellular development.