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

doi:10.15252/embj.201696290

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

Research output: Contribution to journal › Article › peer-review

38 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 language	English
Pages (from-to)	2146-2160
Number of pages	15
Journal	EMBO Journal
Volume	36
Issue number	14
DOIs	https://doi.org/10.15252/embj.201696290
Publication status	Published - 2017 Jul 14

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)

Access to Document

10.15252/embj.201696290

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

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, vol. 36, no. 14, pp. 2146-2160. https://doi.org/10.15252/embj.201696290

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title = "Autotaxin–lysophosphatidic acid–LPA3 signaling at the embryo-epithelial boundary controls decidualization pathways",

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.",

keywords = "LPA, autotaxin, decidualization, embryo implantation, lysophosphatidic acid",

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

note = "Funding Information: We thank Shionogi pharmaceutical Co., Ltd for the gift of the ATX inhibitor. We also thank Dr Yasumasa Nishito (Core Technology and Research Center, Tokyo Metropolitan Institute of Medical Science) for DNA microarray analysis. The present work was supported partly by AMED-CREST (Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology) for J.A. and M.M., PRESTO (Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology) for A.I., Ministry of Education, Culture, Sports, Science and Technology (MEXT) Grant-in-Aid for Scientific Research for J.A. and M.M. Publisher Copyright: {\textcopyright} 2017 The Authors. Published under the terms of the CC BY 4.0 license",

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T1 - Autotaxin–lysophosphatidic acid–LPA3 signaling at the embryo-epithelial boundary controls decidualization pathways

AU - Aikawa, Shizu

AU - Kano, Kuniyuki

AU - Inoue, Asuka

AU - Wang, Jiao

AU - Saigusa, Daisuke

AU - Nagamatsu, Takeshi

AU - Hirota, Yasushi

AU - Fujii, Tomoyuki

AU - Tsuchiya, Soken

AU - Taketomi, Yoshitaka

AU - Sugimoto, Yukihiko

AU - Murakami, Makoto

AU - Arita, Makoto

AU - Kurano, Makoto

AU - Ikeda, Hitoshi

AU - Yatomi, Yutaka

AU - Chun, Jerold

AU - Aoki, Junken

N1 - Funding Information: We thank Shionogi pharmaceutical Co., Ltd for the gift of the ATX inhibitor. We also thank Dr Yasumasa Nishito (Core Technology and Research Center, Tokyo Metropolitan Institute of Medical Science) for DNA microarray analysis. The present work was supported partly by AMED-CREST (Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology) for J.A. and M.M., PRESTO (Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology) for A.I., Ministry of Education, Culture, Sports, Science and Technology (MEXT) Grant-in-Aid for Scientific Research for J.A. and M.M. Publisher Copyright: © 2017 The Authors. Published under the terms of the CC BY 4.0 license

PY - 2017/7/14

Y1 - 2017/7/14

N2 - 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.

AB - 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.

KW - LPA

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KW - decidualization

KW - embryo implantation

KW - lysophosphatidic acid

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