Autotaxin–lysophosphatidic acid–LPA 3 signaling at the embryo‐epithelial boundary controls decidualization pathways

• Shizu Aikawa ^[1] ; Kuniyuki Kano ^[6] ; Asuka Inoue ^[7] ; Jiao Wang ^[1] ; Daisuke Saigusa ^[8] ; Takeshi Nagamatsu ^[2] ; Yasushi Hirota ^[2] ; Tomoyuki Fujii ^[2] ; Soken Tsuchiya ^[3] ; Yoshitaka Taketomi ^[4] ; Yukihiko Sugimoto ^[9] ; Makoto Murakami ^[10] ; Makoto Arita ^[11] ; Makoto Kurano ^[12] ; Hitoshi Ikeda ^[12] ; Yutaka Yatomi ^[12] ; Jerold Chun ^[5] ; Junken Aoki ^[6]
  1. [1] Tohoku University

     Tohoku University

     Aoba-ku, Japón

     
  2. [2] University of Tokyo

     University of Tokyo

     Japón

     
  3. [3] Kumamoto University

     Kumamoto University

     Chuo-ku, Japón

     
  4. [4] Tokyo Metropolitan Institute of Medical Science

     Tokyo Metropolitan Institute of Medical Science

     Japón

     
  5. [5] Sanford Burnham Prebys Medical Discovery Institute

     Sanford Burnham Prebys Medical Discovery Institute

     Estados Unidos

     
  6. [6] 1 Graduate School of Pharmaceutical Sciences Tohoku University Sendai Miyagi Japan; 2 Japan Agency for Medical Research and Development Core Research for Evolutional Science and Technology (AMED‐CREST) Chiyoda‐ku Tokyo Japan
  7. [7] 1 Graduate School of Pharmaceutical Sciences Tohoku University Sendai Miyagi Japan; 3 Japan Science and Technology Agency Precursory Research for Embryonic Science and Technology (PRESTO) Kawaguchi Saitama Japan
  8. [8] 2 Japan Agency for Medical Research and Development Core Research for Evolutional Science and Technology (AMED‐CREST) Chiyoda‐ku Tokyo Japan; 4 Department of Integrative Genomics Tohoku Medical Megabank Tohoku University Sendai Miyagi Japan
  9. [9] 2 Japan Agency for Medical Research and Development Core Research for Evolutional Science and Technology (AMED‐CREST) Chiyoda‐ku Tokyo Japan; 6 Department of Pharmaceutical Biochemistry Graduate School of Pharmaceutical Sciences Kumamoto University Kumamoto Japan
  10. [10] 2 Japan Agency for Medical Research and Development Core Research for Evolutional Science and Technology (AMED‐CREST) Chiyoda‐ku Tokyo Japan; 7 Tokyo Metropolitan Institute of Medical Science Setagaya‐ku Tokyo Japan; 8 Center for Disease Biology and Integrative Medicine Graduate School of Medicine The University of Tokyo Bunkyo‐ku Tokyo Japan
  11. [11] 9 RIKEN Center for Integrative Medical Sciences Yokohama Kanagawa Japan; 10 Graduate School of Pharmaceutical Sciences Keio University Minato‐ku Tokyo Japan
  12. [12] 2 Japan Agency for Medical Research and Development Core Research for Evolutional Science and Technology (AMED‐CREST) Chiyoda‐ku Tokyo Japan; 11 Department of Clinical Laboratory The University of Tokyo Hospital Bunkyo‐ku Tokyo Japan

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 36, Nº. 14, 2017, págs. 2146-2160
• Idioma: inglés
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• Resumen

  • During pregnancy, up‐regulation of heparin‐binding (HB‐) EGF and cyclooxygenase‐2 (COX‐2) in the uterine epithelium contributes to decidualization, a series of uterine morphological changes required for placental formation and fetal development. Here, we report a key role for the lipid mediator lysophosphatidic acid (LPA) in decidualization, acting through its G‐protein‐coupled receptor LPA 3 in the uterine epithelium. Knockout of Lpar3 or inhibition of the LPA‐producing enzyme autotaxin (ATX) in pregnant mice leads to HB‐EGF and COX‐2 down‐regulation near embryos and attenuates decidual reactions. Conversely, selective pharmacological activation of LPA 3 induces decidualization via up‐regulation of HB‐EGF and COX‐2. ATX and its substrate lysophosphatidylcholine can be detected in the uterine epithelium and in pre‐implantation‐stage embryos, respectively. Our results indicate that ATX–LPA–LPA 3 signaling at the embryo‐epithelial boundary induces decidualization via the canonical HB‐EGF and COX‐2 pathways.