LIN-44/Wnt controls developmental neurite pruning via UNC-43/CaMKII and PKC-2/PKC in Caenorhabditis elegans

During development, many neurons prune their neurites. While many pruning events are activity-dependent, some neurons undergo stereotyped and developmentally regulated neurite pruning, and our understanding of the signaling pathways that mediate this form of pruning remains limited. In this study, using the PDB motor neuron in Caenorhabditis elegans, we show that the Wnt-calcium signaling pathway is required for stereotyped neurite pruning during development. We found that mutants of itr-1/IP3 receptor and two calcium-dependent kinases, unc-43/CaMKII and pkc-2/PKC, exhibit neurite pruning defects. Genetic analysis suggested that they function downstream of lin-44/Wnt in neurite pruning. Human CaMKIIA can induce neurite pruning in C. elegans, and mutations in CaMKII genes in patients with intellectual disabilities affect its pruning function. In vivo calcium imaging revealed that PDB neurites exhibit calcium transients during neurite pruning, which are regulated at least in part by lin-44 and itr-1. Furthermore, we demonstrate that pkc-2 regulates neurite pruning through clathrin-mediated endocytosis. Together, our work reveals the critical functions of Wnt-calcium signaling in neurite pruning.