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Although GPR64 has an important role for male fertility, its physiological roles in the female reproductive system are still unknown. In the present study, immunohistochemical analysis reveals a spatiotemporal expression of GPR64 in the uterus during early pregnancy. Observation of remarkable induction of GPR64 expression in uterine decidual cells points to its potential physiological significance on decidualization. The decidualization of uterine stromal cells is a key event in implantation. Progesterone (P4) signaling is crucial for the decidualization of the endometrial stromal cells for successful pregnancy. Therefore, we examined ovarian steroid hormone regulation of GPR64 expression in the murine uterus. P4 induced GPR64 expression in the epithelial and stromal cells of the uterus in ovariectomized wild-type mice, but not in PRKO mice. ChIP analysis confirmed that PGR proteins were recruited on progesterone response element of  Gpr64  gene in the uteri of wild-type mice treated with P4. Furthermore, the expression of  GPR64  was increased in human endometrial stromal cells (hESCs) during  in vitro  decidualization. Interestingly, small interfering RNA (siRNA)-mediated knockdown of  GPR64  in hESCs remarkably reduced decidualization. These results suggest that  Gpr64  has a crucial role in the decidualization of endometrial stromal cells.

G-protein coupled receptor 64 is required for decidualization of endometrial stromal cells