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Graduate School of Pharmaceutical Sciences4 and Department of Developmental and Medical Technology,5 Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
PRESTO,6 Japan Science and Technology Corporation, Saitama 32-0012, Japan
Helen L. Dorris Institute for Childhood and Adolescent Neuropsychiatric Disorders,7 The Scripps Research Institute,8 La Jolla, California 92037
Obihiro University of Agriculture and Veterinary Medicine,9 Obihiro, Hokkaido 080-8555, Japan
ABSTRACT
In polytocous animals, blastocysts are evenly distributed along each uterine horn and implant. The molecular mechanisms underlying these precise events remain elusive. We recently showed that lysophosphatidic acid (LPA) has critical roles in the establishment of early pregnancy by affecting embryo spacing and subsequent implantation through its receptor, LPA3. Targeted deletion of Lpa3 in mice resulted in delayed implantation and embryo crowding, which is associated with a dramatic decrease in the prostaglandins and prostaglandin-endoperoxide synthase 2 expression levels. Exogenous administration of prostaglandins rescued the delayed implantation but did not rescue the defects in embryo spacing, suggesting the role of prostaglandins in implantation downstream of LPA3 signaling. In the present study, to know how LPA3 signaling regulates the embryo spacing, we determined the time course distribution of blastocysts during the preimplantation period. In wild-type (WT) uteri, blastocysts were distributed evenly along the uterine horns at Embryonic Day 3.8 (E3.8), whereas in the Lpa3-deficient uteri, they were clustered in the vicinity of the cervix, suggesting that the mislocalization and resulting crowding of the embryos are the cause of the delayed implantation. However, embryos transferred singly into E2.5 pseudopregnant Lpa3-deficient uterine horns still showed delayed implantation but on-time implantation in WT uteri, indicating that embryo spacing and implantation timing are two segregated events. We also found that an LPA3-specific agonist induced rapid uterine contraction in WT mice but not in Lpa3-deficient mice. Because the uterine contraction is critical for embryo spacing, our results suggest that LPA3 signaling controls embryo spacing via uterine contraction around E3.5.
embryo spacing, female reproductive tract, growth factors, implantation, LPA3, lysophosphatidic acid, signal transduction, uterus
1Supported by grants to J.A. and H.A. from the National Institute of Biomedical Innovation, PRESTO (Japan Science and Technology Corporation), the 21st Century Center of Excellence Program, and the Ministry of Education, Science, Sports, and Culture of Japan, and to J.C. from the National Institutes of Health, Bethesda, Maryland (NIH ROI HD050685).
Correspondence: 2FAX: 81 22 795 6859; e-mail: jaoki{at}mail.pharm.tohoku.ac.jp
3Current address: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
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