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Estrogen-induced Egr1 is required for P4-dependent counteraction on estrogenic activities for embryo implantation
- 언어ENG
- URLhttps://db.koreascholar.com/Article/Detail/355422
Harmonized actions of ovarian estrogen (E2) and progesterone (P4) regulate cell proliferation and differentiation in the uterus with a spatiotemporal manner. Imbalance between the actions and levels of two major regulators often lead to infertility and gynecological diseases, such as endometriosis and endometrial cancer. While numerous works have shown that reduced expression and/or deletion of uterine factors associated with P4 signaling could disturb uterine physiology, local factor(s) to mediate E2 actions has not been extensively studied yet. Here we demonstrate that early growth response 1 (Egr1), a transcription factor which is rapidly induced in the uterus by E2, is required to maintain coordinated actions of E2 and P4 for uterine receptivity for embryo implantation. Given exogenous gonadotrophins to overcome LHβ deficiency in the pituitary of Egr1(－/－) mice, ovulation, fertilization and embryo development normally occurred in these mice. However, they showed complete failure of embryo implantation with reduced uterine responses to artificial decidualization stimuli. While serum levels of E2 and P4 in Egr1(－/－) mice were comparable, genes regulated by E2 and/or P4 in uterine epithelial cells (ECs) were aberrantly expressed on day 4 of pregnancy. Impaired P4 signaling along with absence of PR in ECs caused hypersensitive E2 responses shown as enhanced expression of E2-responsive genes such Muc1 and Ltf as well as reduced levels of P4-dependent genes, such as Ihh and Areg, in ECs of Egr1(－/－) mice. This is consistent with persistent proliferation in ECs and severely impaired proliferation in stromal cells (SCs) in Egr1(－/－) mice treated with E2+P4. Furthermore, primary co-culture of Egr1(－/－) ECs with Egr1(+/+) SCs and vice versa supported a notion that Egr1 itself is required for proper responses to two major regulators, E2 and P4, in both uterine cell compartments. Collectively, our results show that E2-induced Egr1 participates in P4-dependent modulation on E2 activities in the uterus by regulating a spectrum of genes essential for uterine receptivity and embryo implantation.
