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.

Highlights

  • Wnt signaling in human trophoblastMaternal decidua likely cross-talking to diverse uterine cell types, including uterine natural killer cells, macrophages, and decidual stromal cells (Bulmer et al, 2010; Oreshkova et al, 2012)

  • 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

  • This review focuses on function of Wnt signaling in trophoblast and placental development and differentiation, whereas a number of different papers summarize the role of canonical and noncanonical Wnt signaling in female reproductive tract development and differentiation, uterine function and decidualization (Chen et al, 2009; Sonderegger et al, 2010b; van der Horst et al, 2012; Wetendorf and DeMayo, 2012)

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Summary

Wnt signaling in human trophoblast

Maternal decidua likely cross-talking to diverse uterine cell types, including uterine natural killer cells, macrophages, and decidual stromal cells (Bulmer et al, 2010; Oreshkova et al, 2012). Expression of inhibitor of DNA binding 2 (Id2), blocking the binding activity of differentiation-promoting basic helix-loop-helix (bHLH) proteins through heterodimerisation, was shown to be downregulated in EVTs of normal pregnancy but maintained in preeclamptic placental tissue (Janatpour et al, 2000) Along those lines, inhibition of HIF1α-dependent TGFβ3, acting as a negative regulator of trophoblast invasion, restored migration in explant cultures of preeclamptic villi emphasizing the particular role of oxygen in EVT differentiation (Caniggia et al, 1999, 2000a). Using immunopurified CTBs and EVTs isolated from outgrowths of villous explant cultures and gene chips with a lower number of probe sets compared to the aforementioned study, we detected 991 differentially expressed transcripts in our analyses (Bilban et al, 2009) One of these mRNAs which was found to be induced upon EVT differentiation encoded TCF-4, one of the key transcription factors in Wnt signaling (Roose and Clevers, 1999). Wnt ligands trigger non-canonical, β-catenin-independent signaling including the Wnt/Ca2+ and the Wnt/planar cell polarity (PCP) pathway (Gordon and Nusse, 2006; Hendrickx and Leyns, 2008; van Amerongen and Nusse, 2009)

CANONICAL Wnt SIGNALING
CONCLUSIONS
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