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

Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
Development (Impact Factor: 6.46). 03/2008; 135(4):717-27. DOI: 10.1242/dev.015339
Source: PubMed


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-beta-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-beta-catenin signaling with attenuation of the non-canonical 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.

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Available from: Haibin Wang
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    • "In another study, Dkk1 and a small molecular inhibitor (PKF115– 584) were used to block canonical Wnt signalling in mouse embryo culture (Xie et al. 2008). In that study, silencing of nuclear b-catenin signalling blocked blastocyst competency to implant, whereas the simultaneous activation of canonical Wnt signalling combined with blockade of the non-canonical Wnt/ RhoA signalling pathway confirmed blastocyst competency to implantation (Xie et al. 2008). The environmental toxicant 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD) affects embryo development, implantation and fertility in humans. "
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    ABSTRACT: The integration of a complex network of signalling molecules promotes implantation of the blastocyst and development of the placenta. These processes are crucial for a successful pregnancy and fetal growth and development. The signalling network involves both cell-cell and cell-extracellular matrix communication. The family of secreted glycoprotein ligands, the Wnts, plays a major role in regulating a wide range of biological processes, including embryonic development, cell fate, proliferation, migration, stem cell maintenance, tumour suppression, oncogenesis and tissue homeostasis. Recent studies have provided evidence that Wnt signalling pathways play an important role in reproductive tissues and in early pregnancy events. The focus of this review is to summarise our present knowledge of expression, regulation and function of the Wnt signalling pathways in early pregnancy events of human and other model systems, and its association with pathological conditions. Despite our recent progress, much remains to be learned about Wnt signalling in human reproduction. The advancement of knowledge in this area has applications in the reduction of infertility and the incidence and morbidity of gestational diseases.
    Full-text · Article · Sep 2014 · Reproduction Fertility and Development
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    • "Furthermore, WNT pathway components are responsible for meiotic spindle orientation in Caenorhabditis elegans [9]. Inhibition of the WNT signaling pathway during early embryo development is deleterious in the cow [10], but not the mouse [11]. Interestingly, Dickkopf-related protein 3 (DKK3: thought to be a negative regulator of the WNT signaling pathway) is present in the oocyte and early mouse embryo [6], but it is controversial as to whether or not it is directly involved in the WNT pathway [12], [13]. "
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    ABSTRACT: The ability to mature oocytes in vitro provides a tool for creating embryos by parthenogenesis, fertilization, and cloning. Unfortunately the quality of oocytes matured in vitro falls behind that of in vivo matured oocytes. To address this difference, transcriptional profiling by deep sequencing was conducted on pig oocytes that were either matured in vitro or in vivo. Alignment of over 18 million reads identified 1,316 transcripts that were differentially represented. One pathway that was overrepresented in the oocytes matured in vitro was for Wingless-type MMTV integration site (WNT) signaling. In an attempt to inhibit the WNT pathway, Dickkopf-related protein 1 was added to the in vitro maturation medium. Addition of Dickkopf-related protein 1 improved the percentage of oocytes that matured to the metaphase II stage, increased the number of nuclei in the resulting blastocyst stage embryos, and reduced the amount of disheveled segment polarity protein 1 protein in oocytes. It is concluded that transcriptional profiling is a powerful method for detecting differences between in vitro and in vivo matured oocytes, and that the WNT signaling pathway is important for proper oocyte maturation.
    Full-text · Article · Apr 2014 · PLoS ONE
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    • "Again, development into blastocysts was observed suggesting that β -catenin is not required for early pre-implantation development. Also, treatment with Dkk1 did not impair blastocyst formation (Xie et al., 2008). Non-canonical signaling such as the Wnt/Ca2+ pathway could be involved (Chen et al., 2009). "
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    ABSTRACT: Wingless ligands, a family of secreted proteins, are critically involved in organ development and tissue homeostasis by ensuring balanced rates of stem cell proliferation, cell death and differentiation. Wnt signaling components also play crucial roles in murine placental development controlling trophoblast lineage determination, chorioallantoic fusion and placental branching morphogenesis. However, the role of the pathway in human placentation, trophoblast development and differentiation is only partly understood. Here, we summarize our present knowledge about Wnt signaling in the human placenta and discuss its potential role in physiological and aberrant trophoblast invasion, gestational diseases and choriocarcinoma formation. Differentiation of proliferative first trimester cytotrophoblasts into invasive extravillous trophoblasts is associated with nuclear recruitment of β -catenin and induction of Wnt-dependent T-cell factor 4 suggesting that canonical Wnt signaling could be important for the formation and function of extravillous trophoblasts. Indeed, activation of the pathway was shown to promote trophoblast invasion in different in vitro trophoblast model systems as well as trophoblast cell fusion. Methylation-mediated silencing of inhibitors of Wnt signaling provided evidence for epigenetic activation of the pathway in placental tissues and choriocarcinoma cells. Similarly, abundant nuclear expression of β -catenin in invasive trophoblasts of complete hydatidiform moles suggested a role for hyper-activated Wnt signaling. In contrast, upregulation of Wnt inhibitors was noticed in placentae of women with preeclampsia, a disease characterized by shallow trophoblast invasion and incomplete spiral artery remodeling. Moreover, changes in Wnt signaling have been observed upon cytomegalovirus infection and in recurrent abortions. In summary, the current literature suggests a critical role of Wnt signaling in physiological and abnormal trophoblast function.
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