Hyperactivated Wnt-ß-catenin signaling in the absence of sFRP1 and sFRP5 disrupts trophoblast differentiation through repression of Ascl2.

BACKGROUND: Wnt signaling is a critical determinant for the maintenance and differentiation of stem/progenitor cells, including trophoblast stem cells during placental development. Hyperactivation of Wnt signaling has been shown to be associated with human trophoblast diseases. However, little is known about the impact and underlying mechanisms of excessive Wnt signaling during placental trophoblast development. RESULTS: In the present work, we observed that two inhibitors of Wnt signaling, secreted frizzled-related proteins 1 and 5 (Sfrp1 and Sfrp5), are highly expressed in the extraembryonic trophoblast suggesting possible roles in early placental development. Sfrp1 and Sfrp5 double knockout mice exhibited disturbed trophoblast differentiation in the placental ectoplacental cone (EPC), which contains the precursors of trophoblast giant cells (TGCs) and spongiotrophoblast cells. In addition, we employed mouse models expressing a truncated ß-catenin with exon 3 deletion globally and trophoblast-specifically, as well as trophoblast stem cell lines, and unraveled that hyperactivation of canonical Wnt pathway exhausted the trophoblast precursor cells in the EPC, resulting in the overabundance of giant cells at the expense of spongiotrophoblast cells. Further examination uncovered that hyperactivation of canonical Wnt pathway disturbed trophoblast differentiation in the EPC via repressing Ascl2 expression. CONCLUSIONS: Our investigations provide new insights that the homeostasis of canonical Wnt-ß-catenin signaling is essential for EPC trophoblast differentiation during placental development, which is of high clinical relevance, since aberrant Wnt signaling is often associated with trophoblast-related diseases.

Adgrg1 is a new transcriptional target of Hand1 during trophoblast giant cell differentiation.

The placenta, forming the maternal-fetal interface, is essential for the survival and development of the fetus. It has been shown that the basic helix-loop-helix (bHLH) transcription factor Hand1 plays an important role in trophoblast giant cells (TGCs) differentiation during placental development in mice. However, the underlying molecular mechanism remains elusive. We hereby report that Adgrg1 (GPR56), a G protein coupled receptor, was a new transcriptional target of Hand1. Hand1 activated the expression of Adgrg1 by binding to its promoter region during TGCs differentiation. Double in situ hybridization revealed co-expression of Hand1 and Adgrg1 in Prl2c2+ TGCs located in the junctional zone of the placenta. Knockdown of Adgrg1 not only led to increased Prl2c2 expression, but also the improvement of cell migration and invasion during TGC differentiation. Moreover, the ligand of Adgrg1, Tgm2, was expressed in Prl2c2+ TGCs located in the placental junctional zone and Tgm2 Knockdown increased cell migration and invasion, suggesting Tgm2 is a potential ligand involved in the functions of Adgrg1 during TGC differentiation in the manners of autocrine. Collectively, these results demonstrate that Adgrg1 is a new transcriptional target of Hand1, affecting Prl2c2 expression as well as cell migration and invasion during TGCs differentiation. As a transmembrane receptor, Adgrg1 perhaps could act as a potential therapeutic target for placental-associated diseases caused by abnormal trophoblast migration and invasion, providing new insights for the preventions and therapies of placenta-related diseases.