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LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing

Abstract

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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Acknowledgements

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). https://doi.org/10.1038/nature03505

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