ADAMTS-1: a novel target gene of an estrogen-induced transcription factor, EGR1, critical for embryo implantation in the mouse uterus

Abstract

Background: Recently, 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. Result: The 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. Conclusions: Collectively, 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.