The role of Lrp6-mediated Wnt/ß-catenin signaling in the cause and intervention of spinal neural tube defects in mice

Neural tube defects (NTDs) are among common and severe birth defects with poorly understood etiology. Mutations in the Wnt coreceptor LRP6 are associated with NTDs in humans. Either gain-of-function (GOF) or loss-of-function (LOF) mutations of Lrp6 can cause NTDs in mice. NTDs in Lrp6-GOF mutants may be attributed to altered ß-catenin-independent noncanonical Wnt signaling. However, the mechanisms of NTDs in Lrp6-LOF mutants and the role of Lrp6-mediated canonical Wnt/ß-catenin signaling in neural tube closure remain unresolved. We previously demonstrated that ß-catenin signaling is required for posterior neuropore (PNP) closure. The current study shows that conditional ablation of Lrp6 in dorsal PNP causes spinal NTDs with diminished activities of Wnt/ß-catenin signaling and its downstream target gene Pax3 that is required for PNP closure. ß-catenin-GOF can rescue NTDs in Lrp6-LOF mutants. Moreover, maternal supplementation of a Wnt/ß-catenin signaling agonist can reduce the frequency and severity of spinal NTDs in Lrp6-LOF mutants by restoring Pax3 expression. Together, these results demonstrate the essential role of Lrp6-mediated Wnt/ß-catenin signaling in PNP closure, which may also provide a therapeutic target for NTD intervention through manipulation of canonical Wnt/ß-catenin signaling activities.