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Primarily known for its role as major microtubule organizing center, the centrosome is increasingly being recognized for its functional significance in key cell cycle regulating events. We are now at the beginning of understanding the centrosome’s functional complexities and its major impact on directing complex interactions and signal transduction cascades important for cell cycle regulation. The centrosome orchestrates entry into mitosis, anaphase onset, cytokinesis, G1/S transition, and monitors DNA damage. Recently, the centrosome has also been recognized as major docking station where regulatory complexes accumulate including kinases and phosphatases as well as numerous other cell cycle regulators that utilize the centrosome as platform to coordinate multiple cell cycle-specific functions. Vesicles that are translocated along microtubules to and away from centrosomes may also carry enzymes or substrates that use centrosomes as main docking station. The centrosome’s role in various diseases has been recognized and a wealth of data has been accumulated linking dysfunctional centrosomes to cancer, Alstrom syndrome, various neurological disorders, and others. Centrosome abnormalities and dysfunctions have been associated with several types of infertility. The present review highlights the centrosome’s significant roles in cell cycle events in somatic and reproductive cells and discusses centrosome abnormalities and implications in disease.

The global prevalence of prediabetes and type 2 diabetes (T2D) is increasing, and it is contributing to the susceptibility to diabetes and its related epidemic in offspring. Although the impacts of paternal impaired fasting blood glucose and glucose intolerance on the metabolism of offspring have been well established, the exact molecular and mechanistic basis that mediates these impacts remains largely unclear. Here we show that paternal prediabetes increases the susceptibility to diabetes in offspring through gametic epigenetic alterations. In our findings, paternal prediabetes led to glucose intolerance and insulin resistance in offspring. Relative to controls, offspring of prediabetic fathers exhibited altered gene expression patterns in the pancreatic islets, with down-regulation of several genes involved in glucose metabolism and insulin signaling pathways. Epigenomic profiling of offspring pancreatic islets revealed numerous changes in cytosine methylation depending on paternal prediabetes, including reproducible changes in methylation over several insulin signaling genes. Paternal prediabetes altered overall methylome patterns in sperm, with a large portion of differentially methylated genes overlapping with that of pancreatic islets in offspring. Our study uniquely revealed that prediabetes can be inherited transgenerationally through the mammalian germ line by an epigenetic mechanism.

Mitochondria play vital roles in oocyte functions and they are critical indicators of oocyte quality which is important for fertilization and development into viable offspring. Quality-compromised oocytes are correlated with infertility, developmental disorders, reduced blastocyst cell number and embryo loss in which mitochondrial dysfunctions play a significant role. Increasingly, women affected by metabolic disorders such as diabetes or obesity and oocyte aging are seeking treatment in IVF clinics to overcome the effects of adverse metabolic conditions on mitochondrial functions and new treatments have become available to restore oocyte quality. The past decade has seen enormous advances in potential therapies to restore oocyte quality and includes dietary components and transfer of mitochondria from cells with mitochondrial integrity into mitochondria-impaired oocytes. New technologies have opened up new possibilities for therapeutic advances which will increase the success rates for IVF of oocytes from women with compromised oocyte quality.

The formation of zygote is the beginning of mammalian life, and dynamic epigenetic modifications are essential for mammalian normal development. H3K27 di-methylation (H3K27me2) and H3K27 tri-methylation (H3K27me3) are marks of facultative heterochromatin which maintains transcriptional repression established during early development in many eukaryotes. However, the mechanism underlying establishment and regulation of epigenetic asymmetry in the zygote remains obscure. Here we show that maternal EZH2 is required for the establishment of H3K27me3 in mouse zygotes. However, combined immunostaining with ULI-NChIP-seq (ultra-low-input micrococcal nuclease-based native ChIP-seq) shows that EZH1 could partially safeguard the role of EZH2 in the formation of H3K27me2. Meanwhile, we identify that EHMT1 is involved in the establishment of H3K27me2, and that H3K27me2 might be an essential prerequisite for the following de novo H3K27me3 modification on the male pronucleus. In this work, we clarify the establishment and regulatory mechanisms of H3K27me2 and H3K27me3 in mouse zygotes. Dynamic arrangement of epigenetic modifications such as repressive H3K27 methylation is essential for zygote development. Here the authors show that establishment of genome-wide H3K27me3 in zygotes requires EZH2, that EZH1 partially compensates for EZH2 loss, and that EHMT1 is involved in H3K27me2 establishment.

Protein phosphatase 6 (PP6) is a member of the PP2A-like subfamily, which plays a critical role in many fundamental cellular processes. We recently reported that PP6 is essential for female fertility. Here, we report that PP6 is involved in meiotic recombination and that germ cell-specific deletion of PP6 by Stra8-Cre causes defective spermatogenesis. The PP6-deficient spermatocytes were arrested at the pachytene stage and defects in DSB repair and crossover formation were observed, indicating that PP6 facilitated meiotic double-stranded breaks (DSB) repair. Further investigations revealed that depletion of PP6 in the germ cells affected chromatin relaxation, which was dependent on MAPK pathway activity, consequently preventing programmed DSB repair factors from being recruited to proper positions on the chromatin. Taken together, our results demonstrate that PP6 has an important role in meiotic recombination and male fertility.

In vitro fertilization (IVF) and other assisted reproductive technologies (ART) have become a significant part of human reproduction, with already one in 50 children worldwide being born through ART and the demand steadily increasing. To accommodate the various kinds of infertility problems, new methods have been developed to increase IVF and ART success rates and it has also become possible to treat sperm, eggs, and embryos in culture to improve reproductive success, to increase the health state of an embryo, and to prevent disease in the developing child. Human Reproduction: Updates and New Horizons focuses on recent developments and new approaches to study egg and sperm cells and embryo development, as well as addressing the increasing demand for IVF and ART to overcome infertility problems of various kinds that are encountered by an increasing number of couples worldwide. The book includes 10 chapters written by experts in their specific fields to provide information on sperm selection techniques and their relevance to ART; In vitro maturation of human oocytes: current practices and future promises; Molecular biology of endometriosis; Novel immunological aspects for the treatment of age-induced ovarian and testicular infertility, other functional diseases, and early and advanced cancer immunotherapy; Mitochondrial manipulation for infertility treatment and disease prevention; Novel imaging techniques to assess gametes and preimplantation embryos; Clinical application of methods to select in vitro fertilized embryos; New horizons/developments in time-lapse morphokinetic analysis of mammalian embryos; The non-human primate model for early human development; Cytoskeletal functions, defects, and dysfunctions affecting human fertilization and embryo development. This book will appeal to a large interdisciplinary audience, including researchers from both the basic science and medical communities. It will be a valuable reference for IVF clinicians, patients and prospective patients who are considering ART procedures, embryologists, cell biologists and students in the field of reproduction.

Background Female infertility is a worldwide concern and the etiology of infertility has not been thoroughly demonstrated. Although the mouse is a good model system to perform functional studies, the differences between mouse and human also need to be considered. The objective of this study is to elucidate the different molecular mechanisms underlying oocyte maturation and fertilization between human and mouse. Results A comparative transcriptome analysis was performed to identify the differentially expressed genes and associated biological processes between human and mouse oocytes. In total, 8513 common genes, as well as 15,165 and 6126 uniquely expressed genes were detected in human and mouse MII oocytes, respectively. Additionally, the ratios of non-homologous genes in human and mouse MII oocytes were 37 and 8%, respectively. Functional categorization analysis of the human MII non-homologous genes revealed that cAMP-mediated signaling, sister chromatid cohesin, and cell recognition were the major enriched biological processes. Interestingly, we couldn’t detect any GO categories in mouse non-homologous genes. Conclusions This study demonstrates that human and mouse oocytes exhibit significant differences in gene expression profiles during oocyte maturation, which probably deciphers the differential molecular responses to oocyte maturation and fertilization. The significant differences between human and mouse oocytes limit the generalizations from mouse to human oocyte maturation. Knowledge about the limitations of animal models is crucial when exploring a complex process such as human oocyte maturation and fertilization.

In animals, mtDNA is always transmitted through the female and this is termed “maternal inheritance.” Recently, autophagy was reported to be involved in maternal inheritance by elimination of paternal mitochondria and mtDNA in Caenorhabditis elegans ; moreover, by immunofluorescence, P62 and LC3 proteins were also found to colocalize to sperm mitochondria after fertilization in mice. Thus, it has been speculated that autophagy may be an evolutionary conserved mechanism for paternal mitochondrial elimination. However, by using two transgenic mouse strains, one bearing GFP-labeled autophagosomes and the other bearing red fluorescent protein-labeled mitochondria, we demonstrated that autophagy did not participate in the postfertilization elimination of sperm mitochondria in mice. Although P62 and LC3 proteins congregated to sperm mitochondria immediately after fertilization, sperm mitochondria were not engulfed and ultimately degraded in lysosomes until P62 and LC3 proteins disengaged from sperm mitochondria. Instead, sperm mitochondria unevenly distributed in blastomeres during cleavage and persisted in several cells until the morula stages. Furthermore, by using single sperm mtDNA PCR, we observed that most motile sperm that had reached the oviduct for fertilization had eliminated their mtDNA, leaving only vacuolar mitochondria. However, if sperm with remaining mtDNA entered the zygote, mtDNA was not eliminated and could be detected in newborn mice. Based on these results, we conclude that, in mice, maternal inheritance of mtDNA is not an active process of sperm mitochondrial and mtDNA elimination achieved through autophagy in early embryos, but may be a passive process as a result of prefertilization sperm mtDNA elimination and uneven mitochondrial distribution in embryos.

Our knowledge of reproductive biology has increased enormously in recent years on cellular, molecular, and genetic levels, leading to significant breakthroughs that have directly benefitted in vitro fertilization (IVF) and other assisted reproductive technologies (ART) in humans and animal systems. Animal Models and Human Reproduction presents a comprehensive reference that reflects the latest scientific research being done in human reproductive biology utilizing domestic animal models. Chapters on canine, equine, cow, pig, frog, and mouse models of reproduction reflect frontier research in placental biology, ovarian function and fertility, non-coding RNAs in gametogenesis, oocyte and embryo metabolism, fertilization, cryopreservation, signal transduction pathways, chromatin dynamics, epigenetics, reproductive aging, and inflammation. Chapters on non-human primate models also highlight recent advancements into such issues as human in vitro fertilization (IVF) and assisted reproductive technologies (ART). This book offers animal scientists, reproductive biology scientists, clinicians and practitioners, invaluable insights into a wide range of issues at the forefront of human reproductive health.