Autotaxin–lysophosphatidic acid–LPA3 signaling at the embryo-epithelial boundary controls decidualization pathways

Shizu Aikawa, Kuniyuki Kano, Asuka Inoue, Jiao Wang, Daisuke Saigusa, Takeshi Nagamatsu, Yasushi Hirota, Tomoyuki Fujii, Soken Tsuchiya, Yoshitaka Taketomi, Yukihiko Sugimoto, Makoto Murakami, Makoto Arita, Makoto Kurano, Hitoshi Ikeda, Yutaka Yatomi, Jerold Chun, Junken Aoki

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12 Citations (Scopus)

Abstract

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 LPA3 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 LPA3 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–LPA3 signaling at the embryo-epithelial boundary induces decidualization via the canonical HB-EGF and COX-2 pathways.

Original languageEnglish
Pages (from-to)2146-2160
Number of pages15
JournalEMBO Journal
Volume36
Issue number14
DOIs
Publication statusPublished - 2017 Jul 14

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Keywords

  • LPA
  • autotaxin
  • decidualization
  • embryo implantation
  • lysophosphatidic acid

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Aikawa, S., Kano, K., Inoue, A., Wang, J., Saigusa, D., Nagamatsu, T., Hirota, Y., Fujii, T., Tsuchiya, S., Taketomi, Y., Sugimoto, Y., Murakami, M., Arita, M., Kurano, M., Ikeda, H., Yatomi, Y., Chun, J., & Aoki, J. (2017). Autotaxin–lysophosphatidic acid–LPA3 signaling at the embryo-epithelial boundary controls decidualization pathways. EMBO Journal, 36(14), 2146-2160. https://doi.org/10.15252/embj.201696290