The LIF-mediated molecular signature regulating murine embryo implantation

• Published in: Biology of reproduction Vol. 91; no. 3; p. 66
• Main Authors: Rosario, Gracy X, Hondo, Eiichi, Jeong, Jae-Wook, Mutalif, Rafidah, Ye, Xiaoqian, Yee, Li Xuan, Stewart, Colin L
• Format: Journal Article
• Language: English
• Published: United States 01.09.2014
• Subjects: Animals; Blotting, Western; Chromatin Assembly and Disassembly; Computational Biology; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Dinoprostone - administration & dosage; Dinoprostone - metabolism; Embryo Implantation; Endometrium - cytology; Endometrium - enzymology; Endometrium - metabolism; Female; Gene Expression Profiling; Gene Expression Regulation, Developmental; Injections, Intraperitoneal; Leukemia Inhibitory Factor - administration & dosage; Leukemia Inhibitory Factor - genetics; Leukemia Inhibitory Factor - metabolism; Mice, Inbred C3H; Oligonucleotide Array Sequence Analysis; Real-Time Polymerase Chain Reaction; Recombinant Proteins - administration & dosage; Recombinant Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Signal Transduction; luminal epithelium; LIF; implantation; microarray; uterus
• ISSN: 1529-7268
• DOI: 10.1095/biolreprod.114.118513

The establishment of a receptive uterus is the prime requirement for embryo implantation. In mice, the E2-induced cytokine leukemia inhibitory factor (LIF) is essential in switching the uterine luminal epithelium (LE) from a nonreceptive to a receptive state. Here we define the LIF-mediated switch using array analysis and informatics to identify LIF-induced changes in gene expression and annotated signaling pathways specific to the LE. We compare gene expression profiles at 0, 1, 3, and 6 h, following LIF treatment. During the first hour, the JAK-STAT signaling pathway is activated and the expression of 54 genes declines, primarily affecting LE cytoskeletal and chromatin organization as well as a transient reduction in the progesterone, TGFbetaR1, and ACVR1 receptors. Simultaneously 256 genes increase expression, of which 42 are transcription factors, including Sox, Kfl, Hes, Hey, and Hox families. Within 3 h, the expression of 3987 genes belonging to more than 25 biological process pathways was altered. We confirmed the mRNA and protein distribution of key genes from 10 pathways, including the Igf-1, Vegf, Toll-like receptors, actin cytoskeleton, ephrin, integrins, TGFbeta, Wnt, and Notch pathways. These data identify novel LIF-activated pathways in the LE and define the molecular basis between the refractory and receptive uterine phases. More broadly, these findings highlight the staggering capacity of a single cytokine to induce a dynamic and complex network of changes in a simple epithelium essential to mammalian reproduction and provide a basis for identifying new routes to regulating female reproduction.