Dynamics of Wnt receptor activation, signal initiation and signal termination in vivo

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NSF Proposal IOS-1353799Marcel Wehrli, Ph.D.Dynamics of Wnt receptor activation, signal initiation and signal termination in vivoCells of developing embryos and adult tissues must receive and precisely interpret specific signals for proper growth. Secreted proteins of the Wnt family represent one such signal. Wnts elicit precise changes in gene expression mediated by increased levels of the protein ?beta-catenin. Too much or too little signal leads to tissue defects and disease. While it is known that Wnts activate cell surface receptors, it remains unclear where on the cell membrane or inside the cell the ligand-activated receptor functions, how it activates the intracellular signaling cascade via the protein Dishevelled and how the receptor is turned off. This proposal addresses these questions directly with a novel in vivo approach. In addition, it will identify how Dishevelled blocks the central regulator in the pathway, a protein complex assembled around the scaffold protein Axin, and is expected to identify in vivo how the receptor-initiated signal leads to the inhibition of the Axin complex and induces beta-catenin signaling, a process that remains controversial. Broader ImpactOur understanding of the Wnt/beta-catenin pathway has increased dramatically in recent years. However, many findings are derived from in vitro experiments and their functional significance is limited. The signaling events of the Wnt/beta-catenin pathway are amenable to investigation in their normal cellular context using the Drosophila model system, underscoring the significance of the studies proposed here. These investigations are expected to identify dynamically changing interactions as the signal is transduced, thereby greatly increasing our understanding of this important signaling mechanism.This proposal will provide an opportunity for one graduate student and three undergraduates to engage in cutting edge research. In addition, it will allow the PI to introduce K-12 students to basic development and genetics and to promote a science-based curriculum in local schools.