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

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

doi:10.15252/embj.201696290

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 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.

Highlights

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
We previously showed that LPA3, which is highly expressed in the uterine epithelium during the peri-implantation period (Ye et al, 2005), has a critical role in the early pregnancy
We focused on Hbegf and Ptgs2, because they are responsible for decidualization and knockout of these genes interfered with implantation (Lim et al, 1997; Song et al, 2002; Wang et al, 2004; Xie et al, 2007; Large et al, 2014), as was observed in Lpar3 KO mice (Ye et al, 2005)

Summary

Introduction

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. 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 Lpar 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. 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 embryoepithelial boundary induces decidualization via the canonical HB-EGF and COX-2 pathways

Methods

Results

Conclusion