Estrogen induces EGR1 to fine‐tune its actions on uterine epithelium by controlling PR signaling for successful embryo implantation

Abstract

The harmonized actions of ovarian E and progesterone (P) regulate the proliferation and differentiation of uterine cells in a spatiotemporal manner. Imbalances between these hormones often lead to infertility and gynecologic diseases. Whereas numerous factors that are involved in P signaling have been identified, few local factors that mediate E actions in the uterus have been revealed. Here, we demonstrate that estrogen induces the transcription factor, early growth response 1 ( Egr1), to fine-tune its actions in uterine epithelial cells (ECs) that are responsible for uterine receptivity for embryo implantation. In the presence of exogenous gonadotrophins, ovulation, fertilization, and embryonic development normally occur in Egr1 mice, but these animals experience the complete failure of embryo implantation with reduced artificial decidualization. Although serum levels of E and P were comparable between Egr1 and Egr1 mice on d 4 of pregnancy, aberrantly reduced levels of progesterone receptor in Egr1 uterine ECs caused enhanced E activity and impaired P response. Ultrastructural analyses revealed that Egr1 ECs are not fully able to provide proper uterine receptivity. Uterine mRNA landscapes in Egr1 mice revealed that EGR1 controls the expression of a subset of E-regulated genes. In addition, P signaling was unable to modulate estrogen actions, including those that are involved in cell-cycle progression, in ECs that were deficient in EGR1. Furthermore, primary coculture of Egr1 ECs with Egr1 stromal cells, and vice versa, supported the notion that Egr1 is required to modulate E actions on ECs to prepare the uterine environment for embryo implantation. In contrast to its role in ECs, loss of Egr1 in stroma significantly reduced stromal cell proliferation. Collectively, our results demonstrate that E induces EGR1 to streamline its actions for the preparation of uterine receptivity for embryo implantation in mice.-Kim, H.-R., Kim, Y. S., Yoon, J. A., Yang, S. C., Park, M., Seol, D.-W., Lyu, S. W., Jun, J. H., Lim, H. J., Lee, D. R., Song, H. Estrogen induces EGR1 to fine-tune its actions on uterine epithelium by controlling PR signaling for successful embryo implantation.

Uterine receptivity, embryo attachment, and embryo invasion: Multistep processes in embryo implantation

“…EGR1 is induced in both epithelial cells and stromal cells by E 2 through the ERα‐ERK1/2 pathway in the uterus (Figure ) and also induced in the subluminal stromal cells surrounding the implanting blastocyst . In EGR1 null mice, the expression of PR in epithelial cells is aberrantly reduced, E 2 activity is enhanced, and P 4 response is impaired . Furthermore, the uterus of EGR1 null mice demonstrated continuous proliferation of luminal epithelial cells and poor proliferation of stromal cells, indicating that impaired uterine PDS in EGR1 null mice.…”

“…Furthermore, the uterus of EGR1 null mice demonstrated continuous proliferation of luminal epithelial cells and poor proliferation of stromal cells, indicating that impaired uterine PDS in EGR1 null mice. These findings suggest that E 2 induces EGR1 to fine‐tune its actions on uterine epithelium by controlling P 4 ‐PR signaling in order to acquire uterine receptivity …”

“…Another recent study showed that early growth response 1 (EGR1) null female mice are completely infertile due to implantation failure . EGR1 belongs to the EGR family of zinc finger transcription factors which participate in the regulation of cell proliferation, differentiation, and apoptosis .…”

Secretory phospholipase A2-X (Pla2g10) is a novel progesterone receptor target gene exclusively induced in uterine luminal epithelium for uterine receptivity in mice

“…Molecular cross-talks between the blastocyst and the uterus induce growth factors, adhesion molecules, cytokines, and transcription factors to prepare uterine conditions for embryo implantation [6,[28][29][30][31]. P 4 -PR-target gene networks are known to have critical functions for embryo implantation [8,32,33].…”

“…Uterine samples during early pregnancy were prepared as previously described [31]. Brie y, 8-to 10-weekold female mice were housed with proven fertile males for pregnancy.…”