Phosphatidylinositol 3-kinase signaling in mammalian preimplantation embryo development

The development of the preimplantation mammalian embryo is an autopoietic process; once initiated development proceeds without an absolute requirement for external information or growth cues. This developmental autonomy is partly explained by the generation of autocrine trophic ligands that are released and act back on the embryo via specific receptors. Several embryotrophic ligands cause receptor-dependent activation of 1-o-phosphatidylinositol 3-kinase. This enzyme phosphorylates phosphatidylinositol-4,5-bisphosphate to form phosphatidylinositol-3,4,5-trisphosphate. Genetic or pharmacological ablation of this enzyme activity disrupts normal development of preimplantation embryos. Phosphatidylinositol-3,4,5-trisphosphate is a membrane lipid that acts as a docking site for a wide range of proteins possessing the pleckstrin homology (PH) domain. Such proteins are important regulators of cell survival, proliferation, and differentiation. RAC-α serine/threonine protein kinase is an important PH domain protein and its activity is required for normal preimplantation embryo development and survival. The activity of a range of PH domain proteins is also implicated in the normal development of the embryo. This review critically examines the evidence for the activation of 1-o-phosphatidylinositol 3-kinase in the generation of pleiotypic trophic response to embryotrophins in the autopoietic development of the preimplantation embryo.

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Inhibition of DRP1 Impedes Zygotic Genome Activation and Preimplantation Development in Mice

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.788512 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yuanyuan Li ◽

Ning-Hua Mei ◽

Gui-Ping Cheng ◽

Jing Yang ◽

Li-Quan Zhou

Keyword(s):

Embryo Development ◽

Preimplantation Embryo ◽

Preimplantation Embryos ◽

Dependent Manner ◽

Zygotic Genome Activation ◽

Preimplantation Embryo Development ◽

Cell Embryo ◽

Embryo Stage ◽

Genome Activation ◽

Zygotic Genome

Mitochondrion plays an indispensable role during preimplantation embryo development. Dynamic-related protein 1 (DRP1) is critical for mitochondrial fission and controls oocyte maturation. However, its role in preimplantation embryo development is still lacking. In this study, we demonstrate that inhibition of DRP1 activity by mitochondrial division inhibitor-1, a small molecule reported to specifically inhibit DRP1 activity, can cause severe developmental arrest of preimplantation embryos in a dose-dependent manner in mice. Meanwhile, DRP1 inhibition resulted in mitochondrial dysfunction including decreased mitochondrial activity, loss of mitochondrial membrane potential, reduced mitochondrial copy number and inadequate ATP by disrupting both expression and activity of DRP1 and mitochondrial complex assembly, leading to excessive ROS production, severe DNA damage and cell cycle arrest at 2-cell embryo stage. Furthermore, reduced transcriptional and translational activity and altered histone modifications in DRP1-inhibited embryos contributed to impeded zygotic genome activation, which prevented early embryos from efficient development beyond 2-cell embryo stage. These results show that DRP1 inhibition has potential cytotoxic effects on mammalian reproduction, and DRP1 inhibitor should be used with caution when it is applied to treat diseases. Additionally, this study improves our understanding of the crosstalk between mitochondrial metabolism and zygotic genome activation.

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Intracellular oxygen metabolism during bovine oocyte and preimplantation embryo development

Scientific Reports ◽

10.1038/s41598-021-99512-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Paul J. McKeegan ◽

Selina F. Boardman ◽

Amy A. Wanless ◽

Grace Boyd ◽

Laura J. Warwick ◽

...

Keyword(s):

Mitochondrial Dna ◽

Oxygen Consumption ◽

Oxygen Concentration ◽

Embryo Development ◽

Preimplantation Embryo ◽

Complex Iii ◽

Preimplantation Embryos ◽

Mitochondrial Oxygen Consumption ◽

Preimplantation Embryo Development

AbstractWe report a novel method to profile intrcellular oxygen concentration (icO2) during in vitro mammalian oocyte and preimplantation embryo development using a commercially available multimodal phosphorescent nanosensor (MM2). Abattoir-derived bovine oocytes and embryos were incubated with MM2 in vitro. A series of inhibitors were applied during live-cell multiphoton imaging to record changes in icO2 associated with mitochondrial processes. The uncoupler carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) uncouples mitochondrial oxygen consumption to its maximum, while antimycin inhibits complex III to ablate mitochondrial oxygen consumption. Increasing oxygen consumption was expected to reduce icO2 and decreasing oxygen consumption to increase icO2. Use of these inhibitors quantifies how much oxygen is consumed at basal in comparison to the upper and lower limits of mitochondrial function. icO2 measurements were compared to mitochondrial DNA copy number analysed by qPCR. Antimycin treatment increased icO2 for all stages tested, suggesting significant mitochondrial oxygen consumption at basal. icO2 of oocytes and preimplantation embryos were unaffected by FCCP treatment. Inner cell mass icO2 was lower than trophectoderm, perhaps reflecting limitations of diffusion. Mitochondrial DNA copy numbers were similar between stages in the range 0.9–4 × 106 copies and did not correlate with icO2. These results validate the MM2 probe as a sensitive, non-toxic probe of intracellular oxygen concentration in mammalian oocytes and preimplantation embryos.

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Islet transplantation reverses the effects of maternal diabetes on mouse oocytes

Reproduction ◽

10.1530/rep-10-0370 ◽

2011 ◽

Vol 141 (4) ◽

pp. 417-424 ◽

Cited By ~ 15

Author(s):

Pan-Pan Cheng ◽

Jun-Jie Xia ◽

Hai-Long Wang ◽

Ji-Bing Chen ◽

Fei-Yu Wang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Islet Transplantation ◽

Embryo Development ◽

Oocyte Maturation ◽

Preimplantation Embryo ◽

Maternal Diabetes ◽

Meiotic Spindle ◽

Preimplantation Embryos ◽

Preimplantation Embryo Development ◽

Parthenogenetic Activation

Maternal diabetes adversely affects preimplantation embryo development and oocyte maturation. Thus, it is important to identify ways to eliminate the effects of maternal diabetes on preimplantation embryos and oocytes. The objectives of this study were to investigate whether islet transplantation could reverse the effects of diabetes on oocytes. Our results revealed that maternal diabetes induced decreased ovulation; increased the frequency of meiotic spindle defects, chromosome misalignment, and aneuploidy; increased the relative expression levels of Mad2 and Bub1; and enhanced the sensitivity of oocytes to parthenogenetic activation. Islet transplantation prevented these detrimental effects. Therefore, we concluded that islet transplantation could reverse the effects of diabetes on oocytes, and that this technique may be useful to treat the fundamental reproductive problems of women with diabetes mellitus.

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Mitochondria in early development: linking the microenvironment, metabolism and the epigenome

Reproduction ◽

10.1530/rep-18-0431 ◽

2019 ◽

Vol 157 (5) ◽

pp. R159-R179 ◽

Cited By ~ 23

Author(s):

Alexandra J Harvey

Keyword(s):

Embryo Development ◽

Cell Function ◽

Preimplantation Embryo ◽

Atp Synthesis ◽

Mitochondrial Activity ◽

Long Term Effects ◽

Critical Function ◽

Preimplantation Embryo Development ◽

Wide Range

Mitochondria, originally of bacterial origin, are highly dynamic organelles that have evolved a symbiotic relationship within eukaryotic cells. Mitochondria undergo dynamic, stage-specific restructuring and redistribution during oocyte maturation and preimplantation embryo development, necessary to support key developmental events. Mitochondria also fulfil a wide range of functions beyond ATP synthesis, including the production of intracellular reactive oxygen species and calcium regulation, and are active participants in the regulation of signal transduction pathways. Communication between not only mitochondria and the nucleus, but also with other organelles, is emerging as a critical function which regulates preimplantation development. Significantly, perturbations and deficits in mitochondrial function manifest not only as reduced quality and/or poor oocyte and embryo development but contribute to post-implantation failure, long-term cell function and adult disease. A growing body of evidence indicates that altered availability of metabolic co-factors modulate the activity of epigenetic modifiers, such that oocyte and embryo mitochondrial activity and dynamics have the capacity to establish long-lasting alterations to the epigenetic landscape. It is proposed that preimplantation embryo development may represent a sensitive window during which epigenetic regulation by mitochondria is likely to have significant short- and long-term effects on embryo, and offspring, health. Hence, mitochondrial integrity, communication and metabolism are critical links between the environment, the epigenome and the regulation of embryo development.

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Hemoglobin: potential roles in the oocyte and early embryo†

Biology of Reproduction ◽

10.1093/biolre/ioz078 ◽

2019 ◽

Vol 101 (2) ◽

pp. 262-270 ◽

Cited By ~ 1

Author(s):

Megan Lim ◽

Hannah M Brown ◽

Karen L Kind ◽

Jeremy G Thompson ◽

Kylie R Dunning

Keyword(s):

Embryo Development ◽

Oocyte Maturation ◽

Preimplantation Embryo ◽

Cell Types ◽

Cellular Function ◽

Preimplantation Embryos ◽

Low Oxygen ◽

Preimplantation Embryo Development ◽

Regulated Gene Expression

Abstract Hemoglobin (Hb) is commonly known for its capacity to bind and transport oxygen and carbon dioxide in erythroid cells. However, it plays additional roles in cellular function and health due to its capacity to bind other gases including nitric oxide. Further, Hb acts as a potent antioxidant, quenching reactive oxygen species. Despite its potential roles in cellular function, the preponderance of Hb research remains focused on its role in oxygen regulation. There is increasing evidence that Hb expression is more ubiquitous than previously thought, with Hb and its variants found in a myriad of cell types ranging from macrophages to spermatozoa. The majority of nonerythroid cell types that express Hb are situated within hypoxic environments, suggesting Hb may play a role in hypoxia-inducible factor-regulated gene expression by controlling the level of oxygen available or as an adaptation to low oxygen providing a mechanism to store oxygen. Oocyte maturation and preimplantation embryo development occur within the low oxygen environments of the antral follicle and oviduct/uterus, respectively. Interestingly, Hb was recently found in human cumulus and granulosa cells and murine cumulus–oocyte complexes and preimplantation embryos. Here, we consolidate and analyze the research generated todate on Hb expression in nonerythroid cells with a particular focus on reproductive cell types. We outline future directions of this research to elucidate the role of Hb during oocyte maturation and preimplantation embryo development and finally, we explore the potential clinical applications and benefits of Hb supplementation during the in vitro culture of gametes and embryos.

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Whole-Genome DNA Methylation Dynamics of Sheep Preimplantation Embryo Investigated by Single-Cell DNA Methylome Sequencing

Frontiers in Genetics ◽

10.3389/fgene.2021.753144 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zijing Zhang ◽

Jiawei Xu ◽

Shijie Lyu ◽

Xiaoling Xin ◽

Qiaoting Shi ◽

...

Keyword(s):

Dna Methylation ◽

Single Cell ◽

Embryo Development ◽

Molecular Mechanisms ◽

Preimplantation Embryo ◽

Preimplantation Embryos ◽

Whole Genome ◽

Cell Stage ◽

Preimplantation Embryo Development ◽

Developmental Block

The early stages of mammalian embryonic development involve the participation and cooperation of numerous complex processes, including nutritional, genetic, and epigenetic mechanisms. However, in embryos cultured in vitro, a developmental block occurs that affects embryo development and the efficiency of culture. Although the block period is reported to involve the transcriptional repression of maternal genes and transcriptional activation of zygotic genes, how epigenetic factors regulate developmental block is still unclear. In this study, we systematically analyzed whole-genome methylation levels during five stages of sheep oocyte and preimplantation embryo development using single-cell level whole genome bisulphite sequencing (SC-WGBS) technology. Then, we examined several million CpG sites in individual cells at each evaluated developmental stage to identify the methylation changes that take place during the development of sheep preimplantation embryos. Our results showed that two strong waves of methylation changes occurred, namely, demethylation at the 8-cell to 16-cell stage and methylation at the 16-cell to 32-cell stage. Analysis of DNA methylation patterns in different functional regions revealed a stable hypermethylation status in 3′UTRs and gene bodies; however, significant differences were observed in intergenic and promoter regions at different developmental stages. Changes in methylation at different stages of preimplantation embryo development were also compared to investigate the molecular mechanisms involved in sheep embryo development at the methylation level. In conclusion, we report a detailed analysis of the DNA methylation dynamics during the development of sheep preimplantation embryos. Our results provide an explanation for the complex regulatory mechanisms underlying the embryo developmental block based on changes in DNA methylation levels.

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Demilune Cell and Parotid Protein from Murine Oviductal Epithelium Stimulates Preimplantation Embryo Development

Endocrinology ◽

10.1210/en.2005-0596 ◽

2006 ◽

Vol 147 (1) ◽

pp. 79-87 ◽

Cited By ~ 22

Author(s):

Kai-Fai Lee ◽

Jia-Sen Xu ◽

Yin-Lau Lee ◽

William S. B. Yeung

Keyword(s):

Gene Expression ◽

Embryo Development ◽

Preimplantation Embryo ◽

Expression Patterns ◽

Mrna Level ◽

Mouse Embryos ◽

Preimplantation Embryos ◽

Preimplantation Embryo Development ◽

Ovariectomized Mice ◽

Oviductal Epithelium

In mammals, fertilization and early preimplantation embryo development occur in the oviduct. We hypothesized that interaction exists between the developing embryos and the maternal genital tract, such that the embryos modulate the physiology and gene expression of the oviduct so that it is conducive to their development. By comparing the gene expression patterns in mouse oviducts containing transferred preimplantation embryos with those of oviducts containing oocytes, we report here the characterization of demilune cell and parotid protein (Dcpp), which was up-regulated in the embryo-containing oviduct. Dcpp mRNA was highly expressed in the oviductal epithelium at the estrus stage. The Dcpp gene codes for a protein of 150 amino acids and contains a signal peptide suggestive of secretory function. The Dcpp mRNA level was maintained in the oviductal epithelium of pregnant females but decreased continuously in those of pseudopregnant mice. Exogenous estrogen stimulated the expression of Dcpp mRNA and protein in ovariectomized mice. The effect was abolished by an estrogen antagonist, ICI 182,780. Dcpp protein was present in mouse oviductal fluid but not in uterine fluid. More importantly, Dcpp immunoreactivity was found in embryos recovered from the oviduct but not in mature oocytes from the ovary. Supplementation of Dcpp to culture medium stimulated the development of mouse embryos to the blastocyst stage. Anti-Dcpp antibody decreased the beneficial effect of Dcpp on implantation of two-cell mouse embryos transferred to the oviducts of the foster mothers. In summary, our data demonstrated that Dcpp is highly expressed in the oviductal lumen in the presence of preimplantation embryos. It stimulates the growth of preimplantation embryos and may play an important role in embryo-maternal dialogue.

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