Wnt-Frizzled signalling in synaptic assembly during development

Our central aim now is to understand how Wnt ligands promote the assembly of synapses through their Frizzled (Fz) receptors. We found that neuronal activity promotes the surface localisation of Fz to the membrane and to synapses. Importantly, this process requires Wnt ligands (Sahores et al., Development 2010). We recently discovered that Fz receptors are S-acylated/palmitoylated, a post-translational modification (PTM). Palmitoylation of Fz5 is increased by chemical long-term-potentiation (cLTP), resulting in an increased level of the receptor at the cell surface (Teo et al, Developmental Cell, 2023). We also found that Fz5 is palmitoylated on three C-terminal cysteines by the acyltransferase zDHHC5. Our findings shed new light on the mechanisms that control the trafficking of Wnt receptors in activity-mediated synapse assembly.

Our previous results showed that LTP promotes the presence of Wnt7a at synapses. Thus, the coordinated regulation of Wnt ligands and the localisation of their receptors is likely to contribute to the specific assembly of synapses in the nervous system. Currently, our focus is to understand the mechanisms that regulate Wnt release and Fz trafficking using live-imaging techniques. We also use mutagenesis approaches to determine the domains of Fz5 required for trafficking as well as gain- and loss-of-function studies. For in vivo experiments, we use stereotactic injections of AAV viruses into the hippocampus that express wildtype and mutant Fz5 receptors, which exhibit defects in trafficking.