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. 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. 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.

中文翻译：

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ADAMTS-1：雌激素诱导转录因子 EGR1 的新靶基因，对小鼠子宫中的胚胎植入至关重要

最近，我们证明雌激素 (E2) 诱导早期生长反应 1 (Egr1) 以通过控制孕酮受体信号传导来介导其对子宫上皮细胞的作用，从而成功植入胚胎。EGR1 是一种转录因子，可调节包括子宫在内的许多不同组织中的靶基因谱。E2 诱导的 EGR1 调节一组参与子宫胚胎植入过程中上皮细胞重塑的基因。然而，仅鉴定了子宫中 EGR1 的少数靶基因。具有血小板反应蛋白 1 型基序 1 (Adamts-1) 的 ADAM 金属肽酶的表达在 E2 处理的卵巢切除 (OVX) Egr1(-/-) 小鼠的子宫中显着下调。ADAMTS-1 的免疫染色显示其在 OVX 野生型而非 Egr1(-/-) 小鼠的子宫上皮中的独家表达。Adamts-1 和 Egr1 的表达谱在 E2 处理的 OVX 小鼠的子宫中在测试的不同时间点相似。用核雌激素受体 (ER) 拮抗剂 ICI 182、780 进行预处理，可有效抑制 Egr1 和 Adamts-1 的 E2 依赖性诱导。E2 诱导的 ERK1/2 或 p38 磷酸化的药理学抑制干扰了 EGR1 和 ADAMTS-1 的诱导。此外，在胚胎植入过程中，ADAMTS-1 以及 EGR1 在植入囊胚周围的基质细胞中被诱导。EGR1 表达载体的瞬时转染显着诱导 ADAMTS-1 的表达。EGR1 以剂量依赖性方式增加了含有 EGR1 结合位点 (EBS) 的 Adamts-1 启动子的荧光素酶活性，表明 EGR1 对 Adamts-1 转录的功能调节。Adamts-1 启动子上 EBS 的定点诱变表明，EGR1 在四个假定的 EBS 中的 -1151/-1134 处直接与 EBS 结合。总的来说，我们已经证明 Adamts-1 是 E2-ER-MAPK-EGR1 的一个新靶基因，这对于妊娠早期小鼠子宫中的胚胎植入至关重要。