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.