We have recently demonstrated that neuroepithelial beta-catenin is required for caudal neural tube closure by regulating critical downstream transcription factors Pax3 and Cdx2 in the dorsal neural folds. Our unpublished data demonstrate that conditional ablation of a key WNT coreceptor LRP6 in neuroepithelial cells of the dorsal neural folds also causes spina bifida with diminished expression of Pax3 and Cdx2, which are similar as seen in the neuroepithelial beta-catenin mutants. We demonstrate that genetic activation of beta-catenin in the dorsal neural folds can rescue neural tube closure defects in the conditional Lrp6 mutant mice. These results demonstrate a previously undetermined role of canonical Wnt/beta-catenin signaling pathway in caudal neural tube closure. To further address the roles of Wnt/beta-catenin signaling in neural tube closure and underlying mechanisms, we have generated novel mutants by conditional gene-targeting in the non-neural surface ectodermal cells. Our preliminary results demonstrate that surface ectodermal Wnt/beta-catenin signaling is required for the closure processes of the entire neural tube, which may mainly act through regulation of F-actin-based cytoskeleton dynamics. Because beta-catenin is also a cell adhesion molecule, we have preliminarily addressed the undetermined role of cell adhesion in neural tube closure. Our results reveal novel mechanisms underlying mammalian neural tube closure, which may provide a basis for better understanding and addressing the cause and prevention of neural tube closure defects in humans.