title: The LIF-mediated molecular signature regulating murine embryo implantation.
abstract: 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.
authors.affiliation: Developmental and Regenerative Biology, Institute of Medical Biology, A*STAR, Immunos, Singapore.
authors.forename: Gracy X
authors.initials: GX
authors.lastname: Rosario
authors.affiliation: Laboratory of Animal Morphology, Division of Biofunctional Development, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Hondo
authors.affiliation: Department of Obstetrics and Gynecology and Reproductive Biology, Michigan State University, Grand Rapids, Michigan.
authors.forename: Jae-Wook
authors.initials: JW
authors.lastname: Jeong
authors.affiliation: Developmental and Regenerative Biology, Institute of Medical Biology, A*STAR, Immunos, Singapore.
authors.forename: Rafidah
authors.initials: R
authors.lastname: Mutalif
authors.affiliation: Developmental and Regenerative Biology, Institute of Medical Biology, A*STAR, Immunos, Singapore.
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Ye
authors.affiliation: Developmental and Regenerative Biology, Institute of Medical Biology, A*STAR, Immunos, Singapore.
authors.forename: Li Xuan
authors.initials: LX
authors.lastname: Yee
authors.affiliation: Developmental and Regenerative Biology, Institute of Medical Biology, A*STAR, Immunos, Singapore colin.stewart@imb.a-star.edu.sg.
authors.forename: Colin L
authors.initials: CL
authors.lastname: Stewart
mesh_terms: D000818:Animals; D015153:Blotting, Western; D042002:Chromatin Assembly and Disassembly; D019295:Computational Biology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000008:administration & dosage / Q000378:metabolism; D010064:Embryo Implantation; D004717:Endometrium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D007274:Injections, Intraperitoneal; D053605:Leukemia Inhibitory Factor / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D008809:Mice, Inbred C3H; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D003598:Cytoskeletal Proteins; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D012333:RNA, Messenger; D011994:Recombinant Proteins; D015232:Dinoprostone
keywords: LIF; implantation; luminal epithelium; microarray; uterus