Abstract
BackgroundRecently, we demonstrated that estrogen (E2) induces early growth response 1 (Egr1) to mediate its actions on the uterine epithelium by controlling progesterone receptor signaling for successful embryo implantation. EGR1 is a transcription factor that regulates the spectrum of target genes in many different tissues, including the uterus. E2-induced EGR1 regulates a set of genes involved in epithelial cell remodeling during embryo implantation in the uterus. However, only few target genes of EGR1 in the uterus have been identified.ResultThe expression of ADAM metallopeptidase with thrombospondin type 1 motif 1 (Adamts-1) was significantly downregulated in the uteri of E2-treated ovariectomized (OVX) Egr1(−/−) mice. Immunostaining of ADAMTS-1 revealed its exclusive expression in the uterine epithelium of OVX wild-type but not Egr1(−/−) mice treated with E2. The expression profiles of Adamts-1 and Egr1 were similar in the uteri of E2-treated OVX mice at various time points tested. Pre-treatment with ICI 182, 780, a nuclear estrogen receptor (ER) antagonist, effectively inhibited the E2-dependent induction of Egr1 and Adamts-1. Pharmacologic inhibition of E2-induced ERK1/2 or p38 phosphorylation interfered with the induction of EGR1 and ADAMTS-1. Furthermore, ADAMTS-1, as well as EGR1, was induced in stroma cells surrounding the implanting blastocyst during embryo implantation. Transient transfection with EGR1 expression vectors significantly induced the expression of ADAMTS-1. Luciferase activity of the Adamts-1 promoter containing EGR1 binding sites (EBSs) was increased by EGR1 in a dose-dependent manner, suggesting functional regulation of Adamts-1 transcription by EGR1. Site-directed mutagenesis of EBS on the Adamts-1 promoter demonstrated that EGR1 directly binds to the EBS at -1151/-1134 among four putative EBSs.ConclusionsCollectively, we have demonstrated that Adamts-1 is a novel target gene of E2-ER-MAPK-EGR1, which is critical for embryo implantation in the mouse uterus during early pregnancy.
Highlights
We demonstrated that estrogen (E2) induces early growth response 1 (Egr1) to mediate its actions on the uterine epithelium by controlling progesterone receptor signaling for successful embryo implanta‐ tion
Collectively, we have demonstrated that Adamts-1 is a novel target gene of E 2-estrogen receptor (ER)-MAPK-EGR1, which is critical for embryo implantation in the mouse uterus during early pregnancy
The results of reverse transcription (RT)-PCR and real-time RT-PCR showed that the expression of Adamts-1 was significantly reduced in the uteri of Egr1(−/−) mice treated with E 2 for 3 h (Fig. 1a)
Summary
We demonstrated that estrogen (E2) induces early growth response 1 (Egr1) to mediate its actions on the uterine epithelium by controlling progesterone receptor signaling for successful embryo implanta‐ tion. EGR1 is a transcription factor that regulates the spectrum of target genes in many different tissues, including the uterus. E2-induced EGR1 regulates a set of genes involved in epithelial cell remodeling during embryo implantation in the uterus. It. Park et al Cell Biosci (2021) 11:155 functions either as a tumor suppressor or oncogene, depending on the cell type and environmental conditions [4]. Park et al Cell Biosci (2021) 11:155 functions either as a tumor suppressor or oncogene, depending on the cell type and environmental conditions [4] Several growth factors, such as Igf-II, PdgfA, and Tgf-β1, have been identified as direct targets of EGR1 in various tissues and pathological contexts including cancers [5,6,7,8]. Only few target genes of EGR1 in the uterus have been identified
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