Inactivation of nuclear Wnt-β-catenin signaling limits blastocyst competency for implantation

Abstract

The activation of the blastocyst, a process by which it gains competency to attach with the receptive uterus, is a prerequisite for successful implantation. However, the molecular basis of blastocyst activation remains largely unexplored. Combining molecular, pharmacological and physiological approaches, we show here that silencing of Wnt-␤-catenin signaling in mice does not adversely affect the development of preimplantation embryos to blastocysts and uterine preparation for receptivity, but, remarkably, blocks blastocyst competency to implantation. Using the physiologically relevant delayed implantation model and trophoblast stem cells in culture, we further demonstrate that a coordinated activation of canonical Wnt-␤-catenin signaling with attenuation of the noncanonical Wnt-RhoA signaling pathway ensures blastocyst competency to implantation. These findings constitute novel evidence that Wnt signaling is at least one pathway that determines blastocyst competency for implantation.

Cell signaling in trophoblast-uterine communication

“…Inhibition of the Wnt/b-catenin pathway prevents implantation (Mohamed et al, 2005). Interestingly, it has been shown that interruption of nuclear b-catenin signaling in the developing embryo does not adversely affect the development of the embryo to the blastocyst stage; however it does interfere with implantation (Xie et al, 2008). Through embryo transfer experiments, these investigators found that implantation failure is due to silencing of the canonical pathway in the blastocyst rather than its deficiency in the acquisition of uterine receptivity.…”

REVIEW ARTICLE: Governing the Invasive Trophoblast: Current Aspects on Intra‐ and Extracellular Regulation

“…In mice, various Wnts and Fzds were detected at the time of implantation, 79 and blastocyst attachment was shown to induce endometrial Wnt-4 expression. 80 Accordingly, blocking of the canonical Wnt pathway with the soluble inhibitors secreted frizzled-related protein 2 (sFRP-2) 81 or Dickkopf-1 (Dkk1), 82 which blocks Wnt signalling upon binding to LRP-5 ⁄ 6, impaired frequency of mouse implantation.…”

The role of Wnt signaling members in the uterus and embryo during pre-implantation and implantation

“…Reciprocal embryo transfer experiments also revealed that silencing of Wnt-β-catenin pathway negatively affected blastocysts' competency to implant [80].…”

“…In blastocyst trophoectoderm cells, Wnt antagonist Dkk1 was downregulated, while canonical ligand Wnt3a was induced at higher levels, leading to intracellular accumulation of dephospho β-catenin [80]. It was found that activation of Wnt/β-catenin pathway by LiCl, inhibited trophoectoderm cell proliferation whereas inhibition of Wnt/β-catenin pathway by Dkk1 induced trophoectoderm cell proliferation [81].…”