Skip to main content
SpringerLink
Log in

Molecular and cellular events involved in the completion of blastocyst implantation

  • Review Article
  • Published:
Reproductive Medicine and Biology

Abstract

Blastocyst implantation is an interactive process between the embryo and the uterus. The synchronization of embryonic development with uterine differentiation to a receptive state is essential for a successful pregnancy. The period of uterine receptivity for implantation is limited. Although implantation involves the interaction of numerous signaling molecules, our understanding of the hierarchical mechanisms that coordinate with the embryo–uterine dialogue is not yet sufficient to prevent infertility caused by implantation failure. This review highlights our knowledge on uterine receptivity and hormonal regulation of blastocyst implantation in mice. We also discuss the adhesion molecules, cross-linker proteins, extracellular proteins, and matricellular proteins involved in blastocyst implantation. Furthermore, our recent study reveals that selective proteolysis in an activated blastocyst is associated with the completion of blastocyst implantation after embryo transfer. A better understanding of uterine and blastocyst biology during the peri-implantation period would facilitate further development of reproductive technology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Dey SK, Lim H, Das SK, Reese J, Paria BC, Daikoku T, et al. Molecular cues to implantation. Endocr Rev. 2004;25:341–73.

    Article  CAS  PubMed  Google Scholar 

  2. Matsumoto H, Sato E. Uterine angiogenesis during implantation and decidualization in mice. Reprod Med Biol. 2006;5:81–6.

    Article  CAS  Google Scholar 

  3. Wang H, Dey SK. Roadmap to embryo implantation: clues from mouse models. Nat Rev Genet. 2006;7:185–99.

    Article  PubMed  Google Scholar 

  4. Matsumoto H, Fukui E, Yoshizawa M. Uterine angiogenesis during implantation in mice. J Mamm Ova Res. 2007;24:45–9.

    Article  Google Scholar 

  5. Matsumoto H, Fukui E, Yoshizawa M. Differential interactions between embryo and uterus during implantation in laboratory animals. J Mamm Ova Res. 2009;26:111–5.

    Article  Google Scholar 

  6. Cha J, Sun X, Dey SK. Mechanisms of implantation: strategies for successful pregnancy. Nat Med. 2012;18:1754–67.

    Article  CAS  PubMed  Google Scholar 

  7. Egashira M, Hirota Y. Uterine receptivity and embryo–uterine interactions in embryo implantation: lessons from mice. Reprod Med Biol. 2013;12:127–32.

    Article  Google Scholar 

  8. Matsumoto H, Fukui E, Yoshizawa M. Angiogenesis and hormonal regulation on uterine receptivity for blastocyst implantation. J Mamm Ova Res. (in press).

  9. Paria BC, Reese J, Das SK, Dey SK. Deciphering the cross-talk of implantation: advances and challenges. Science. 2002;296:2185–8.

    Article  CAS  PubMed  Google Scholar 

  10. Red-Horse K, Zhou Y, Genbacev O, Prakobphol A, Foulk R, McMaster M, et al. Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface. J Clin Invest. 2004;114:744–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. McCormack JT, Greenwald GS. Evidence for a preimplantation rise in oestradiol-17 beta levels on day 4 of pregnancy in the mouse. J Reprod Fertil. 1974;41:297–301.

    Article  CAS  PubMed  Google Scholar 

  12. Paria BC, Huet-Hudson YM, Dey SK. Blastocyst’s state of activity determines the “window” of implantation in the receptive mouse uterus. Proc Natl Acad Sci USA. 1993;90:10159–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Huet-Hudson YM, Andrews GK, Dey SK. Cell type-specific localization of c-myc protein in the mouse uterus: modulation by steroid hormones and analysis of the periimplantation period. Endocrinology. 1989;125:1683–90.

    Article  CAS  PubMed  Google Scholar 

  14. Ma WG, Song H, Das SK, Paria BC, Dey SK. Estrogen is a critical determinant that specifies the duration of the window of uterine receptivity for implantation. Proc Natl Acad Sci USA. 2003;100:2963–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Matsumoto H, Ezoe K, Mitsui A, Fukui E, Ochi M, Yoshizawa M. Vitrified-warmed ovarian tissue autotransplantation into ovariectomized mice restores sufficient ovarian function to support full-term pregnancy. Reprod Med Biol. 2011;10:185–91.

    Article  Google Scholar 

  16. Matsumoto H, Ezoe K, Mitsui A, Fukui E, Ochi M, Yoshizawa M. Extended uterine receptivity for blastocyst implantation and full-term fetal development in mice with vitrified–warmed ovarian tissue autotransplantation. Reprod Med Biol. 2012;11:123–8.

    Article  CAS  Google Scholar 

  17. Yoshinaga K, Adams CE. Delayed implantation in the spayed, progesterone treated adult mouse. J Reprod Fertil. 1966;12:593–5.

    Article  CAS  PubMed  Google Scholar 

  18. Hamatani T, Daikoku T, Wang H, Matsumoto H, Carter MG, Ko MS, et al. Global gene expression analysis identifies molecular pathways distinguishing blastocyst dormancy and activation. Proc Natl Acad Sci USA. 2004;101:10326–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Paria BC, Das SK, Andrews GK, Dey SK. Expression of the epidermal growth factor receptor gene is regulated in mouse blastocysts during delayed implantation. Proc Natl Acad Sci USA. 1993;90:55–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Raab G, Kover K, Paria BC, Dey SK, Ezzell RM, Klagsbrun M. Mouse preimplantation blastocysts adhere to cells expressing the transmembrane form of heparin-binding EGF-like growth factor. Development. 1996;122:637–45.

    CAS  PubMed  Google Scholar 

  21. Paria BC, Lim H, Wang XN, Liehr J, Das SK, Dey SK. Coordination of differential effects of primary estrogen and catecholestrogen on two distinct targets mediates embryo implantation in the mouse. Endocrinology. 1998;139:5235–46.

    CAS  PubMed  Google Scholar 

  22. Paria BC, Das SK, Dey SK. The preimplantation mouse embryo is a target for cannabinoid ligand-receptor signaling. Proc Natl Acad Sci USA. 1995;92:9460–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang H, Guo Y, Wang D, Kingsley PJ, Marnett LJ, Das SK, et al. Aberrant cannabinoid signaling impairs oviductal transport of embryos. Nat Med. 2004;10:1074–80.

    Article  CAS  PubMed  Google Scholar 

  24. Guo Y, Wang H, Okamoto Y, Ueda N, Kingsley PJ, Marnett LJ, et al. N-acylphosphatidylethanolamine-hydrolyzing phospholipase D is an important determinant of uterine anandamide levels during implantation. J Biol Chem. 2005;280:23429–32.

    Article  CAS  PubMed  Google Scholar 

  25. Paria BC, Song H, Wang X, Schmid PC, Krebsbach RJ, Schmid HH, et al. Dysregulated cannabinoid signaling disrupts uterine receptivity for embryo implantation. J Biol Chem. 2001;276:20523–8.

    Article  CAS  PubMed  Google Scholar 

  26. Wang H, Matsumoto H, Guo Y, Paria BC, Roberts RL, Dey SK. Differential G protein-coupled cannabinoid receptor signaling by anandamide directs blastocyst activation for implantation. Proc Natl Acad Sci USA. 2003;100:14914–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Stachecki JJ, Armant DR. Transient release of calcium from inositol 1,4,5-trisphosphate-specific stores regulates mouse preimplantation development. Development. 1996;122:2485–96.

    CAS  PubMed  Google Scholar 

  28. Wang J, Mayernik L, Schultz JF, Armant DR. Acceleration of trophoblast differentiation by heparin-binding EGF-like growth factor is dependent on the stage-specific activation of calcium influx by ErbB receptors in developing mouse blastocysts. Development. 2000;127:33–44.

    CAS  PubMed  Google Scholar 

  29. Wang Y, Wang F, Sun T, Trostinskaia A, Wygle D, Puscheck E, et al. Entire mitogen activated protein kinase (MAPK) pathway is present in preimplantation mouse embryos. Dev Dyn. 2004;231:72–87.

    Article  CAS  PubMed  Google Scholar 

  30. Riley JK, Carayannopoulos MO, Wyman AH, Chi M, Ratajczak CK, Moley KH. The PI3 K/Akt pathway is present and functional in the preimplantation mouse embryo. Dev Biol. 2005;284:377–86.

    Article  CAS  PubMed  Google Scholar 

  31. Aplin JD. Adhesion molecules in implantation. Rev Reprod. 1997;2:84–93.

    Article  CAS  PubMed  Google Scholar 

  32. Aplin JD, Singh H. Bioinformatics and transcriptomics studies of early implantation. Ann N Y Acad Sci. 2008;1127:116–20.

    Article  PubMed  Google Scholar 

  33. Toyama-Sorimachi N, Sorimachi H, Tobita Y, Kitamura F, Yagita H, Suzuki K, et al. A novel ligand for CD44 is serglycin, a hematopoietic cell lineage-specific proteoglycan. Possible involvement in lymphoid cell adherence and activation. J Biol Chem. 1995;270:7437–44.

    Article  CAS  PubMed  Google Scholar 

  34. Yonemura S, Tsukita S, Tsukita S. Direct involvement of ezrin/radixin/moesin (ERM)-binding membrane proteins in the organization of microvilli in collaboration with activated ERM proteins. J Cell Biol. 1999;145:1497–509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Matsumoto H, Daikoku T, Wang H, Sato E, Dey SK. Differential expression of ezrin/radixin/moesin (ERM) and ERM-associated adhesion molecules in the blastocyst and uterus suggests their functions during implantation. Biol Reprod. 2004;70:729–36.

    Article  CAS  PubMed  Google Scholar 

  36. Armant DR, Kaplan HA, Lennarz WJ. Fibronectin and laminin promote in vitro attachment and outgrowth of mouse blastocysts. Dev Biol. 1986;116:519–23.

    Article  CAS  PubMed  Google Scholar 

  37. Carson DD, Tang JP, Gay S. Collagens support embryo attachment and outgrowth in vitro: effects of the Arg-Gly-Asp sequence. Dev Biol. 1988;127:368–75.

    Article  CAS  PubMed  Google Scholar 

  38. Sutherland AE, Calarco PG, Damsky CH. Expression and function of cell surface extracellular matrix receptors in mouse blastocyst attachment and outgrowth. J Cell Biol. 1988;106:1331–48.

    Article  CAS  PubMed  Google Scholar 

  39. Yelian FD, Edgeworth NA, Dong LJ, Chung AE, Armant DR. Recombinant entactin promotes mouse primary trophoblast cell adhesion and migration through the Arg-Gly-Asp (RGD) recognition sequence. J Cell Biol. 1993;121:923–9.

    Article  CAS  PubMed  Google Scholar 

  40. Wordinger RJ, Brun-Zinkernagel AM, Jackson T. An ultrastructural study of in vitro interaction of guinea-pig and mouse blastocysts with extracellular matrices. J Reprod Fertil. 1991;93:585–97.

    Article  CAS  PubMed  Google Scholar 

  41. Li S, Edgar D, Fassler R, Wadsworth W, Yurchenco PD. The role of laminin in embryonic cell polarization and tissue organization. Dev Cell. 2003;4:613–24.

    Article  CAS  PubMed  Google Scholar 

  42. Bedzhov I, Zernicka-Goetz M. Self-organizing properties of mouse pluripotent cells initiate morphogenesis upon implantation. Cell. 2014;156:1032–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Salamat M, Miosge N, Herken R. Development of Reichert’s membrane in the early mouse embryo. Anat Embryol (Berl). 1995;192:275–81.

    Article  CAS  Google Scholar 

  44. Verheijen MH, Defize LH. Signals governing extraembryonic endoderm formation in the mouse: involvement of the type 1 parathyroid hormone-related peptide (PTHrP) receptor, p21Ras and cell adhesion molecules. Int J Dev Biol. 1999;43:711–21.

    CAS  PubMed  Google Scholar 

  45. Blankenship TN, Given RL. Loss of laminin and type IV collagen in uterine luminal epithelial basement membranes during blastocyst implantation in the mouse. Anat Rec. 1995;243:27–36.

    Article  CAS  PubMed  Google Scholar 

  46. Bornstein P, Sage EH. Matricellular proteins: extracellular modulators of cell function. Curr Opin Cell Biol. 2002;14:608–16.

    Article  CAS  PubMed  Google Scholar 

  47. Mukai K, Mitani F, Nagasawa H, Suzuki R, Suzuki T, Suematsu M, et al. An inverse correlation between expression of a preprocathepsin B-related protein with cysteine-rich sequences and steroid 11beta -hydroxylase in adrenocortical cells. J Biol Chem. 2003;278:17084–92.

    Article  CAS  PubMed  Google Scholar 

  48. Li D, Mukai K, Suzuki T, Suzuki R, Yamashita S, Mitani F, et al. Adrenocortical zonation factor 1 is a novel matricellular protein promoting integrin-mediated adhesion of adrenocortical and vascular smooth muscle cells. FEBS J. 2007;274:2506–22.

    Article  CAS  PubMed  Google Scholar 

  49. Igarashi T, Tajiri Y, Sakurai M, Sato E, Li D, Mukai K, et al. Tubulointerstitial nephritis antigen-like 1 is expressed in extraembryonic tissues and interacts with laminin 1 in the Reichert membrane at postimplantation in the mouse. Biol Reprod. 2009;81:948–55.

    Article  CAS  PubMed  Google Scholar 

  50. Sakurai M, Sato Y, Mukai K, Suematsu M, Fukui E, Yoshizawa M, et al. Distribution of tubulointerstitial nephritis antigen-like 1 and structural matrix proteins in mouse embryos during preimplantation development in vivo and in vitro. Zygote. 2014;22:259–65.

    Article  CAS  PubMed  Google Scholar 

  51. Tajiri Y, Igarashi T, Li D, Mukai K, Suematsu M, Fukui E, et al. Tubulointerstitial nephritis antigen-like 1 is expressed in the uterus and binds with integrins in decidualized endometrium during postimplantation in mice. Biol Reprod. 2010;82:263–70.

    Article  CAS  PubMed  Google Scholar 

  52. Saito K, Furukawa E, Kobayashi M, Fukui E, Yoshizawa M, Matsumoto H. Degradation of estrogen receptor in activated blastocysts is associated with implantation in the delayed implantation mouse model. Mol Hum Reprod. 2014;20:384–91.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the Japan Society for the Promotion of Science (JSPS) Kakenhi program (grant nos. 22580316 and 25450390 to H.M.) and the Joint Research Project of the Japan-US Cooperative Science Program (to H.M.).

Author information

Authors and Affiliations

  1. Laboratory of Animal Breeding and Reproduction, Division of Animal Science, Faculty of Agriculture, Utsunomiya University, Utsunomiya, Tochigi, 321-8505, Japan

    Hiromichi Matsumoto, Emiko Fukui & Midori Yoshizawa

  2. Center for Bioscience Research and Education, Utsunomiya University, Utsunomiya, Tochigi, 321-8505, Japan

    Hiromichi Matsumoto, Emiko Fukui & Midori Yoshizawa

Authors
  1. Hiromichi Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emiko Fukui
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Midori Yoshizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hiromichi Matsumoto.

Ethics declarations

Conflict of interest

Hiromichi Matsumoto, Emiko Fukui and Midori Yoshizawa declare that they have no conflicts of interest.

Human rights and informed consent

This article does not contain any studies with human subjects.

Animal studies

All institutional and national guidelines for the care and use of animals were followed.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Matsumoto, H., Fukui, E. & Yoshizawa, M. Molecular and cellular events involved in the completion of blastocyst implantation. Reprod Med Biol 15, 53–58 (2016). https://doi.org/10.1007/s12522-015-0222-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12522-015-0222-8

Keywords

Search

Navigation