Park Mira, Park So Hee, Park Hyunsun, Kim Hye-Ryun, Lim Hyunjung J, Song Haengseok
Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-do, 13488, Republic of Korea.
Department of Veterinary Medicine, School of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, South Korea.
Cell Biosci. 2021 Aug 4;11(1):155. doi: 10.1186/s13578-021-00672-8.
Recently, we demonstrated that estrogen (E) 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. E-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 E-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 E. The expression profiles of Adamts-1 and Egr1 were similar in the uteri of E-treated OVX mice at various time points tested. Pre-treatment with ICI 182, 780, a nuclear estrogen receptor (ER) antagonist, effectively inhibited the E-dependent induction of Egr1 and Adamts-1. Pharmacologic inhibition of E-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 E-ER-MAPK-EGR1, which is critical for embryo implantation in the mouse uterus during early pregnancy.
最近，我们证明雌激素（E）通过控制孕激素受体信号传导来诱导早期生长反应1（Egr1），从而介导其对子宫上皮的作用，以实现成功的胚胎着床。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。E诱导的EGR1调节一组参与子宫胚胎着床期间上皮细胞重塑的基因。然而，子宫中EGR1的靶基因仅被鉴定出少数几个。
在雌激素处理的去卵巢（OVX）Egr1基因敲除（-/-）小鼠的子宫中，含血小板反应蛋白基序的金属蛋白酶1（Adamts-1）的表达显著下调。对ADAMTS-1的免疫染色显示，其仅在雌激素处理的OVX野生型小鼠而非Egr1基因敲除（-/-）小鼠的子宫上皮中表达。在测试的不同时间点，雌激素处理的OVX小鼠子宫中Adamts-1和Egr1的表达谱相似。用核雌激素受体（ER）拮抗剂ICI 182,780预处理可有效抑制雌激素依赖性的Egr1和Adamts-1诱导。对雌激素诱导的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，在胚胎着床期间，着床胚泡周围的基质细胞中诱导了ADAMTS-1以及EGR1。用EGR1表达载体进行瞬时转染可显著诱导ADAMTS-1的表达。含EGR1结合位点（EBSs）的Adamts-1启动子的荧光素酶活性被EGR1以剂量依赖性方式增加，表明EGR1对Adamts-1转录具有功能性调节。对Adamts-1启动子上EBS的定点诱变表明，EGR1直接与四个推定EBS中位于-1151/-1134处的EBS结合。
总体而言，我们证明Adamts-1是E-ER-MAPK-EGR1的一个新靶基因，在小鼠妊娠早期子宫胚胎着床过程中起关键作用。
