CryoEM studies of Wnt3a-FZD8-LRP6 signaling complex in neurogenesis and regeneration

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Wnt signaling is crucial both for neuronal neurogenesis and for synaptic plasticity and maintenance in the adult brain. Thus, modulating Wnt-mediated neurogenesis and regeneration represents a promising treatment for both central nervous system injuries and neurodegenerative diseases like Parkinson’s and Alzheimer’s. The canonical Wnt3a signaling pathway plays fundamental role in the medically relevant neurogenesis and regeneration and stem-cell renewal. The central event of the Wnt3a pathway is the formation of Wnt3a-FZD8-LRP6 transmembrane complex, which initiates and transduces the signal from the extracellular side into the intracellular side of the cell membrane. The lack of structural information on the intact Wnt3a-FZD8-LRP6 signaling complex or any other complex structure of their homologs greatly hinders our understanding of molecular mechanisms for this fundamental pathway and impairs the development of Wnt-related regenerative therapeutics. The central goal of this research is to determine the structure-based mechanisms of the canonical Wnt3a-FZD8-LRP6 complex by single particle cryo-EM. The structural study will allow us to visualize the atomic interactions between the Wnt3a ligand and its receptors FZD8 and LRP6, map key structural elements that are responsible for signal transduction, and identify potential locations for future therapeutic molecule development. We will also study the structure of the Wnt3a-FZD8-LRP6 complex that purified from native source and investigate the basis of Wnt ligand selectivity and specificity which is a great puzzle in the field considering there are multiple Wnt ligands and receptors. Additionally, we will apply time-resolved cryo-EM studies to resolve the signal transduction dynamics and visualize the Wnt3a signal transduction in near real time. The results of this research program will not only serve as a foundation for understanding the molecular principles by which other Wnt ligands induce signal transduction and related pathological mechanisms in multiple types of diseases including cancer, but also pave the way for the rational design of next-generation therapies for degenerative diseases and injuries.