Egr1 Protein Acts Downstream of Estrogen-Leukemia Inhibitory Factor (LIF)-STAT3 Pathway and Plays a Role during Implantation through Targeting Wnt4

• Published in: The Journal of biological chemistry Vol. 289; no. 34; pp. 23534 - 23545
• Main Authors: Liang, Xiao-Huan, Deng, Wen-Bo, Li, Ming, Zhao, Zhen-Ao, Wang, Tong-Song, Feng, Xu-Hui, Cao, Yu-Jing, Duan, En-Kui, Yang, Zeng-Ming
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.08.2014; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Base Sequence; Chromatin Immunoprecipitation; Developmental Biology; DNA Primers; Early Growth Response Protein 1 - genetics; Early Growth Response Protein 1 - metabolism; Embryo Implantation; Estrogens - metabolism; Female; Fluorescent Antibody Technique; Gene Knockdown Techniques; In Situ Hybridization; Leukemia Inhibitory Factor - metabolism; Mice; Real-Time Polymerase Chain Reaction; STAT3 Transcription Factor - metabolism; Wnt4 Protein - metabolism; Early Growth Response Protein 1 (Egr1); Embryo Implantation, Uterus, Decidualization; Transcription Factor; Mouse; Estrogen; STAT3
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.588897

Embryo implantation is a highly synchronized process between an activated blastocyst and a receptive uterus. Successful implantation relies on the dynamic interplay of estrogen and progesterone, but the key mediators underlying embryo implantation are not fully understood. Here we show that transcription factor early growth response 1 (Egr1) is regulated by estrogen as a downstream target through leukemia inhibitory factor (LIF) signal transducer and activator of transcription 3 (STAT3) pathway in mouse uterus. Egr1 is localized in the subluminal stromal cells surrounding the implanting embryo on day 5 of pregnancy. Estrogen rapidly, markedly, and transiently enhances Egr1 expression in uterine stromal cells, which fails in estrogen receptor α knock-out mouse uteri. STAT3 is phosphorylated by LIF and subsequently recruited on Egr1 promoter to induce its expression. Our results of Egr1 expression under induced decidualization in vivo and in vitro show that Egr1 is rapidly induced after deciduogenic stimulus. Egr1 knockdown can inhibit in vitro decidualization of cultured uterine stromal cells. Chromatin immunoprecipitation data show that Egr1 is recruited to the promoter of wingless-related murine mammary tumor virus integration site 4 (Wnt4). Collectively, our study presents for the first time that estrogen regulates Egr1 expression through LIF-STAT3 signaling pathway in mouse uterus, and Egr1 functions as a critical mediator of stromal cell decidualization by regulating Wnt4.