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Wnt signaling has been classified as canonical Wnt/β-catenin-dependent or non-canonical planar cell polarity (PCP) pathway. Misregulation of either pathway is linked mainly to cancer or neural tube defects (NTDs), respectively. Both pathways seem to antagonize each other, and recent studies have implicated a number of molecular switches that activate one pathway while simultaneously inhibiting the other thereby partially mediating this antagonism. The lipoprotein receptor-related proteinLrp6is crucial for the activation of the Wnt/β-catenin pathway, but its function in Wnt/PCP signaling remains largely unknown. In this study, we investigate the role ofLrp6as a molecular switch between both Wnt pathways in a novel ENU mouse mutant ofLrp6(Skax26m1Jus) and in human NTDs. We demonstrate thatSkax26m1Jusrepresents a hypermorphic allele ofLrp6with increased Wnt canonical and abolished PCP-induced JNK activities. We also show thatLrp6Skax26-Jusgenetically interacts with a PCP mutant (Vangl2Lp) where double heterozygotes showed an increased frequency of NTDs and defects in cochlear hair cells' polarity. Importantly, our study also demonstrates the association of rare and novel missense mutations inLRP6that is an inhibitor rather than an activator of the PCP pathway with human NTDs. We show that threeLRP6mutations in NTDs led to a reduced Wnt canonical activity and enhanced PCP signaling. Our data confirm an inhibitory role ofLrp6in PCP signaling in neurulation and indicate the importance of a tightly regulated and highly dosage-sensitive antagonism between both Wnt pathways in this process.