Fig. 5.1
Adverse pregnancy outcomes stemming from aberrant peri-implantation events. Defects in uterine receptivity, attachment reaction, or implantation timing can result in immediate failure of implantation (i) or decidualization (ii) or can perpetuate adverse ripple effects through the remaining stages of pregnancy. These adverse events can lead to deferred attachment/implantation (iii), resulting in embryo crowding, conjoined placenta, placental insufficiency, fetal growth restriction, fetal resorption, and reduced litter size, whereas suboptimal decidualization (iv) can lead to premature decidual senescence, resulting in preterm birth with neonatal death. Poor decidualization can lead to abnormal guidance of placentation and shallow invasion (v), resulting in preeclampsia. ADM adrenomedullin, Arrowhead, blastocyst, Bmp2 bone morphogenetic protein 2, CB1 cannabinoid receptor 1, COUP–TFII chicken ovalbumin upstream promoter–transcription factor-2, Cox2 cyclooxygenase-2, cPLA2α cytosolic phospholipase A2α, DEDD death effector domain-containing protein, Em embryo, ge glandular epithelium, Hand2 heart- and neural crest derivative-expressed protein 2, Hoxa10 homeobox A10, IHH Indian hedgehog, IL11R interleukin 11 receptor α, Klf5 Kruppel-like factor 5, le luminal epithelium, LIF leukemia inhibitory factor, LPA3 lysophosphatidic acid 3, Msx1 muscle segment homeobox 1, mTORC1 mammalian target of rapamycin complex 1, myo myometrium, p53 transformation-related protein p53, ROR receptor tyrosine kinase-like orphan receptor, s stroma, Sgk1 serum- and glucocorticoid-inducible kinase 1. Dotted lines, adverse ripple effects (The images in this figure are adapted from our previous studies (Daikoku et al. 2011; Hirota et al. 2010; Song et al. 2000))
5.6 Future Considerations
While several interesting aspects of embryo–uterine interactions in implantation and subsequent pregnancy events have been reported, there is still much to be uncovered. It is now evident that the quality of early pregnancy events (in particular, specific stages of implantation) has profound effects on the later stages of pregnancy and its success. Studies in mutant mice have repeatedly shown that inferior embryo implantation perpetuates adverse ripple effects that lead to defective implantation, abnormal embryo spacing, suboptimal progression through decidualization, and placentation, leading to compromised pregnancy outcome (reviewed in (Cha et al. 2012)).
Studies using animal models to determine optimal molecular signatures during uterine receptivity for implantation may be clinically significant in humans, since poor uterine receptivity is a major cause of pregnancy failure in IVF programs. However, in order for this signature to be elucidated in humans, the precise timing of implantation and sequence of implantation events must be identified. Although many molecular players appear similar between mouse and human, the exact timing of their expression during the peri-implantation period in humans is unknown. Studies in subhuman primates may provide more mechanistic information in this regard. Furthermore, molecular programming to initiate the transition from the receptive to refractory phase has not been elucidated. Investigating this transition may allow lengthening of the receptive phase in humans.
In addition to better defining the molecular landscape of uterine receptivity prior to attachment, embryonic signals heralding attachment of the blastocyst to the uterine lining remain to be determined. While increased vascular permeability is considered a marker of implantation in rodents and many other species, this may be the end result of earlier molecular interactions. HB-EGF is considered the earliest known molecular mediator of embryo–uterine interactions; however, additional factors expressed either in sequence or in parallel have yet to be explored. These factors could perhaps be identified by high fidelity or in situ mass spectrometry at specific times prior to attachment reaction (Burnum et al. 2009).
Finally, new insights in the epigenetic regulation of chromatin remodeling, gene expression, and long noncoding RNAs (lncRNA) in implantation and decidualization have come to light, such as miRNA regulation of Cox2 (Chakrabarty et al. 2007). Furthermore, miRNA regulation of reproductive organs has been implicated in various stages of pregnancy, such as implantation and parturition timing (Liu et al. 2011; Renthal et al. 2013). DNA methylation in the context of decidual polyploidy has shown to be a requirement in hormone-dependent gene expression, shedding new light on the dynamic gene expression profiles seen in the pregnant uterus under the influence of hormones (Gao et al. 2012). In addition, the transmission of epigenetic programming from mother to future generations has also been studied in the context of dietary deficiencies (Jirtle and Skinner 2007). How the maternal environment influences the reproductive capability of future generations has yet to be investigated.
This chapter is in honor of Roger Short and his seminal contributions to the field of reproduction. After completing a bachelor’s degree in veterinary science at Bristol University and earning a PhD in reproductive endocrinology at Cambridge University, Roger Short was fascinated by animal reproduction and became involved with the World Health Organization with special interest in contraceptive research, regulation of reproduction, and human population growth. One of his many interests included the consistent timing of mating behavior in animals in different hemispheres. This observation led to the identification of the influence of light on the pineal gland to trigger the secretion of melatonin. Known to test hypotheses on himself, he tested melatonin as a sleep aid, and it is now regularly used to prevent jet lag. With advances in clock gene biology and recent identification of central and peripheral clocks in reproductive tissues (Miller et al. 2004; Reiter et al. 2014), the influence of the melatonin, local and central clocks, and their roles in reproduction are worthy endeavors to study. Indeed, with the recent emergence in gene knockout technology, proteomics, mass spectrometry, single-cell analysis, and bioinformatics, much information can be gleaned to study Roger Short’s unique observations and adventurous thoughts to further elucidate the orchestration of events required for uterine receptivity and implantation for pregnancy success.
Acknowledgments
We thank Serenity Curtis for her help in editing this review article. The work described from Dey lab has been funded by NIH. We regret that space limitations precluded us from citing many relevant references.
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