title: Embryo spacing and implantation timing are differentially regulated by LPA3-mediated lysophosphatidic acid signaling in mice.
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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Hama
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.forename: Asuka
authors.initials: A
authors.lastname: Inoue
authors.forename: Tomoko
authors.initials: T
authors.lastname: Endo
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Amano
authors.forename: Rie
authors.initials: R
authors.lastname: Motoki
authors.forename: Motomu
authors.initials: M
authors.lastname: Kanai
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Ye
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.forename: Norio
authors.initials: N
authors.lastname: Matsuki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Shibasaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
mesh_terms: D000818:Animals; D010064:Embryo Implantation / Q000502:physiology*; D005260:Female; D008246:Lysophospholipids / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000502:physiology*; D049368:Receptors, Lysophosphatidic Acid / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors; D014590:Uterine Contraction / Q000502:physiology*