Further Development 12.9: Escape from the Zona Pellucida and Implantation

Birds and Mammals

While the mammalian embryo is moving through the oviduct en route to the uterus, the blastocyst expands within the zona pellucida (the extracellular matrix of the egg that was essential for sperm binding during fertilization; see Chapter 7). During this time, the zona pellucida prevents the blastocyst from adhering to the oviduct walls. (If such adhering occurs—as it sometimes does in humans—it forms an ectopic, or “tubal,” pregnancy, a dangerous condition because an embryo implanted in the oviduct can cause a life-threatening hemorrhage when it begins to grow.) When the embryo reaches the uterus, it must “hatch” from the zona so that it can adhere to the uterine wall.

The mouse blastocyst hatches from the zona pellucida by digesting a small hole in it and squeezing through the hole as the blastocyst expands (Figure 1A). A trypsin-like protease secreted by the trophoblast seems responsible for hatching the blastocyst from the zona (Perona and Wassarman 1986; O’Sullivan et al. 2001). Once outside the zona, the blastocyst can make direct contact with the uterus (Figure 1B). The endometrium—the epithelial lining of the uterus—has been altered by estrogen and progesterone hormones and has made an extensive extracellular matrix that “catches” the blastocyst. This extracellular matrix is composed of complex sugars, collagen, laminin, fibronectin, cadherins, hyaluronic acid, and heparan sulfate receptors (see Ramathal et al. 2011; Tu et al. 2014).

After the initial binding, several other adhesion systems appear to coordinate their efforts to keep the blastocyst tightly bound to the uterine lining. The trophoblast cells synthesize integrins that bind to the uterine collagen, fibronectin, and laminin, and they synthesize heparan sulfate proteoglycan precisely prior to implantation (see Carson et al. 1993). P-cadherins (see Chapter 4) on the trophoblast and uterine endometrium also help dock the embryo to the uterus. Once in contact with the endometrium, Wnt proteins (from the trophoblast, the endometrium, or from both) instruct the trophoblast to secrete a set of proteases, including collagenase, stromelysin, and plasminogen activator. These protein-digesting enzymes digest the extracellular matrix of the uterine tissue, enabling the blastocyst to bury itself within the uterine wall (Strickland et al. 1976; Brenner et al. 1989; Pollheimer et al. 2006).

Figure 1 Hatching from the zona and implantation of the mammalian blastocyst in the uterus. (A) Mouse blastocyst hatching from the zona pellucida. (B) Mouse blastocysts entering the uterus.

Literature Cited

Brenner, C. A., R. R. Adler, D. A. Rappolee, R. A. Pedersen and Z. Werb. 1989. Genes for extracellular-matrix-degrading metalloproteases and their inhibitor, TIMP, are expressed during early mammalian development. Genes Dev. 3: 848–859.

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Carson, D. D., J. P. Tang, J. Julian. 1993. Heparan sulfate proteoglycan (perlecan) expression by mouse embryos during acquisition of attachment competence. Dev Biol 155(1): 97-106. PubMed Link

O’Sullivan, C. M., S. L. Rancourt, S. Y. Liu and D. E. Rancourt. 2001. A novel murine tryptase involved in blastocyst hatching and outgrowth. Reproduction122: 61–71.

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Perona, R. M. and P. M. Wassarman. 1986. Mouse blastocysts hatch in vitro by using a trypsin-like proteinase associated with cells of mural trophectoderm. Dev. Biol. 114: 42–52.

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Pollheimer, J. and 8 others. 2006. Activation of the canonical wingless/T-cell factor signaling pathway promotes invasive differentiation of human trophoblast. Am. J. Pathol. 168: 1134–1147.

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Ramathal, C., W. Wang, E. Hunt, I. C. Bagchi and M. K. Bagchi. 2011. Transcription factor CCAAT enhancer-binding protein beta (C/EBPb) regulates the formation of a unique extracellular matrix that controls uterine stromal differentiation and embryo implantation. J. Biol. Chem. 286: 19860–19871.

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Strickland, S., E. Reich and M. I. Sherman. 1976. Plasminogen activator in early embryogenesis: Enzyme production by trophoblast and parietal endoderm. Cell9: 231–240.

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Tu, Z., H. Ra, S. Zhang, G. Xia, B. Wang and H. Wang. 2014. Molecular determinants of uterine receptivity. Int. J. Dev. Biol. 58: 147–154.

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