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LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing


Every successful pregnancy requires proper embryo implantation. Low implantation rate is a major problem during infertility treatments using assisted reproductive technologies1. Here we report a newly discovered molecular influence on implantation through the lysophosphatidic acid (LPA) receptor LPA3 (refs 2–4). Targeted deletion of LPA3 in mice resulted in significantly reduced litter size, which could be attributed to delayed implantation and altered embryo spacing. These two events led to delayed embryonic development, hypertrophic placentas shared by multiple embryos and embryonic death. An enzyme demonstrated to influence implantation, cyclooxygenase 2 (COX2) (ref. 5), was downregulated in LPA3-deficient uteri during pre-implantation. Downregulation of COX2 led to reduced levels of prostaglandins E2 and I2 (PGE2 and PGI2), which are critical for implantation1. Exogenous administration of PGE2 or carbaprostacyclin (a stable analogue of PGI2) into LPA3-deficient female mice rescued delayed implantation but did not rescue defects in embryo spacing. These data identify LPA3 receptor-mediated signalling as having an influence on implantation, and further indicate linkage between LPA signalling and prostaglandin biosynthesis.

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Figure 1: LPA3 mRNA expression in wild-type uterus and effects of LPA3 deficiency on implantation.
Figure 2: Multiple embryos at individual implantation sites and placental hypertrophy in uteri of LPA3-deficient mice.
Figure 3: Delayed post-implantational development of embryos and increased embryonic death in uteri of LPA3-deficient mice.
Figure 4: Reduced COX2 mRNA and prostaglandin levels in uteri of LPA3-deficient mice, and exogenous prostaglandin rescue of delayed implantation.

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  1. Dey, S. K. et al. Molecular cues to implantation. Endocr. Rev. 25, 341–373 (2004)

    Article  CAS  Google Scholar 

  2. Ishii, I., Fukushima, N., Ye, X. & Chun, J. Lysophospholipid receptors: signaling and biology. Annu. Rev. Biochem. 73, 321–354 (2004)

    Article  CAS  Google Scholar 

  3. Bandoh, K. et al. Molecular cloning and characterization of a novel human G-protein-coupled receptor, EDG7, for lysophosphatidic acid. J. Biol. Chem. 274, 27776–27785 (1999)

    Article  CAS  Google Scholar 

  4. Contos, J. J. & Chun, J. The mouse lp(A3)/Edg7 lysophosphatidic acid receptor gene: genomic structure, chromosomal localization, and expression pattern. Gene 267, 243–253 (2001)

    Article  CAS  Google Scholar 

  5. Lim, H. et al. Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell 91, 197–208 (1997)

    Article  CAS  Google Scholar 

  6. Cleary-Goldman, J. & D'Alton, M. Management of single fetal demise in a multiple gestation. Obstet. Gynecol. Surv. 59, 285–298 (2004)

    Article  Google Scholar 

  7. Umstad, M. P. & Gronow, M. J. Multiple pregnancy: a modern epidemic? Med. J. Aust. 178, 613–615 (2003)

    PubMed  Google Scholar 

  8. Daniel, Y. et al. Analysis of 104 twin pregnancies conceived with assisted reproductive technologies and 193 spontaneously conceived twin pregnancies. Fertil. Steril. 74, 683–689 (2000)

    Article  CAS  Google Scholar 

  9. Wilcox, A. J., Baird, D. D. & Weinberg, C. R. Time of implantation of the conceptus and loss of pregnancy. N. Engl. J. Med. 340, 1796–1799 (1999)

    Article  CAS  Google Scholar 

  10. Tokumura, A., Fukuzawa, K., Yamada, S. & Tsukatani, H. Stimulatory effect of lysophosphatidic acids on uterine smooth muscles of non-pregnant rats. Arch. Int. Pharmacodyn. Ther. 245, 74–83 (1980)

    CAS  PubMed  Google Scholar 

  11. Contos, J. J., Fukushima, N., Weiner, J. A., Kaushal, D. & Chun, J. Requirement for the lpA1 lysophosphatidic acid receptor gene in normal suckling behavior. Proc. Natl Acad. Sci. USA 97, 13384–13389 (2000)

    Article  ADS  CAS  Google Scholar 

  12. Contos, J. J. et al. Characterization of lpa2 (Edg4) and lpa1/lpa2 (Edg2/Edg4) lysophosphatidic acid receptor knockout mice: signaling deficits without obvious phenotypic abnormality attributable to lpa2 . Mol. Cell. Biol. 22, 6921–6929 (2002)

    Article  CAS  Google Scholar 

  13. Kingsbury, M. A., Rehen, S. K., Contos, J. J., Higgins, C. M. & Chun, J. Non-proliferative effects of lysophosphatidic acid enhance cortical growth and folding. Nature Neurosci. 6, 1292–1299 (2003)

    Article  CAS  Google Scholar 

  14. Inoue, M. et al. Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling. Nature Med. 10, 712–718 (2004)

    Article  CAS  Google Scholar 

  15. Noguchi, K., Ishii, S. & Shimizu, T. Identification of p2y9/GPR23 as a novel G protein-coupled receptor for lysophosphatidic acid, structurally distant from the Edg family. J. Biol. Chem. 278, 25600–25606 (2003)

    Article  CAS  Google Scholar 

  16. Paria, B. C., Huet-Hudson, Y. M. & Dey, S. K. Blastocyst's state of activity determines the “window” of implantation in the receptive mouse uterus. Proc. Natl Acad. Sci. USA 90, 10159–10162 (1993)

    Article  ADS  CAS  Google Scholar 

  17. Kennedy, T. G. Evidence for a role for prostaglandins in the initiation of blastocyst implantation in the rat. Biol. Reprod. 16, 286–291 (1977)

    Article  CAS  Google Scholar 

  18. Kinoshita, K. et al. Involvement of prostaglandins in implantation in the pregnant mouse. Adv. Prostaglandin Thromboxane Leukot. Res. 15, 605–607 (1985)

    CAS  PubMed  Google Scholar 

  19. Song, H. et al. Cytosolic phospholipase A2α is crucial for ‘on-time’ embryo implantation that directs subsequent development. Development 129, 2879–2889 (2002)

    CAS  PubMed  Google Scholar 

  20. Frenkian, M., Segond, N., Pidoux, E., Cohen, R. & Jullienne, A. Indomethacin, a COX inhibitor, enhances 15-PGDH and decreases human tumoral C cells proliferation. Prostaglandins 65, 11–20 (2001)

    Article  CAS  Google Scholar 

  21. Reese, J., Brown, N., Paria, B. C., Morrow, J. & Dey, S. K. COX-2 compensation in the uterus of COX-1 deficient mice during the pre-implantation period. Mol. Cell. Endocrinol. 150, 23–31 (1999)

    Article  CAS  Google Scholar 

  22. Sibilia, M. & Wagner, E. F. Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 269, 234–238 (1995)

    Article  ADS  CAS  Google Scholar 

  23. Wang, H. et al. Rescue of female infertility from the loss of cyclooxygenase-2 by compensatory up-regulation of cyclooxygenase-1 is a function of genetic makeup. J. Biol. Chem. 279, 10649–10658 (2004)

    Article  CAS  Google Scholar 

  24. Lim, H. et al. Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARδ. Genes Dev. 13, 1561–1574 (1999)

    Article  CAS  Google Scholar 

  25. Yang, Z. M. et al. Potential sites of prostaglandin actions in the periimplantation mouse uterus: differential expression and regulation of prostaglandin receptor genes. Biol. Reprod. 56, 368–379 (1997)

    Article  CAS  Google Scholar 

  26. Paria, B. C., Song, H. & Dey, S. K. Implantation: molecular basis of embryo-uterine dialogue. Int. J. Dev. Biol. 45, 597–605 (2001)

    CAS  PubMed  Google Scholar 

  27. Gabardi, S. & Cerio, J. Future immunosuppressive agents in solid-organ transplantation. Prog. Transplant. 14, 148–156 (2004)

    Article  Google Scholar 

  28. Ishii, I. et al. Marked perinatal lethality and cellular signaling deficits in mice null for the two sphingosine 1-phosphate (S1P) receptors, S1P2/LPB2/EDG-5 and S1P3/LPB3/EDG-3. J. Biol. Chem. 277, 25152–25159 (2002)

    Article  CAS  Google Scholar 

  29. Hama, K. et al. Lysophosphatidic acid and autotaxin stimulate cell motility of neoplastic and non-neoplastic cells through LPA1. J. Biol. Chem. 279, 17634–17639 (2004)

    Article  CAS  Google Scholar 

  30. Ishii, I. et al. Selective loss of sphingosine 1-phosphate signaling with no obvious phenotypic abnormality in mice lacking its G protein-coupled receptor, LPB3/EDG-3. J. Biol. Chem. 276, 33697–33704 (2001)

    Article  CAS  Google Scholar 

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We thank F. Liu, S. Kupriyanov, R. Rivera, D. Herr, E. Nilsson, M. Murakami, Y. Kita, B. C. Paria, C. Akita, S. Carlson and Q. Chen for technical assistance and suggestions. This work was supported by grants from the National Institute of Mental Health to J.C. and J.J.A.C., the National Institute of Health to M.K.S, Swiss National Science Foundation to B.A., and Program for Promotion of Fundamental Studies in Health Sciences of the Pharmaceuticals and Medical Devices Agency (PMDA) and grants-in-aid from the Ministry of Education, Science, Culture and Sports for the 21st Century Center of Excellence Program, Japan, to H.S., J.A and H.A.

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Correspondence to Jerold Chun.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Table S1

Inheritance of mutated LPA3 allele. (DOC 24 kb)

Supplementary Table S2

Mating study. (DOC 21 kb)

Supplementary Figure S1

Targeted disruption of LPA3. (JPG 155 kb)

Supplementary Figure S2

Verification of loss of LPA3 function after targeted deletion of LPA3. (JPG 713 kb)

Supplementary Figure S3

Expression of LPA3 mRNA in WT uterus. (JPG 131 kb)

Supplementary Figure S4

Identification/characterization of defects in LPA3-deficient female reproduction. (JPG 110 kb)

Supplementary Figure S5

Comparison of placentas from E18.5 control and LPA3-deficient females. (JPG 100 kb)

Supplementary Figure S6

Confirmation of maternal defects for implantation phenotypes. (JPG 651 kb)

Supplementary Figure S7

Expression of LIF, Hoxa-10, and cPLA2α in E3.5 uteri. (JPG 96 kb)

Supplementary Figure S8

Additional information about potential dominant negative effect and genetic background. (JPG 657 kb)

Supplementary Figure Legends

Including figure legends for all 8 Supplementary Figures. (DOC 35 kb)

Supplementary Methods

The Supplementary Methods used to obtain data in Supplementary Figures and additional references. (DOC 42 kb)

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Ye, X., Hama, K., Contos, J. et al. LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing. Nature 435, 104–108 (2005).

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