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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 protein  Lrp6  is 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 of  Lrp6  as a molecular switch between both Wnt pathways in a novel ENU mouse mutant of  Lrp6  ( Skax26 m1Jus  ) and in human NTDs. We demonstrate that  Skax26 m1Jus   represents a hypermorphic allele of  Lrp6  with increased Wnt canonical and abolished PCP-induced JNK activities. We also show that  Lrp6 Skax26-Jus   genetically interacts with a PCP mutant ( Vangl2 Lp  ) 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 in  LRP6  that is an inhibitor rather than an activator of the PCP pathway with human NTDs. We show that three  LRP6  mutations in NTDs led to a reduced Wnt canonical activity and enhanced PCP signaling. Our data confirm an inhibitory role of  Lrp6  in PCP signaling in neurulation and indicate the importance of a tightly regulated and highly dosage-sensitive antagonism between both Wnt pathways in this process.

human molecular genetics

Novel mutations in  Lrp6  orthologs in mouse and human neural tube defects affect a highly dosage-sensitive Wnt non-canonical planar cell polarity pathway