Human female meiosis: what makes a good egg go bad? Trends Genet
School of Molecular Biosciences and Center for Reproductive Biology, Washington State University, Pullman, WA 99164-4660, USA.Trends in Genetics (Impact Factor: 9.92). 03/2008; 24(2):86-93. DOI: 10.1016/j.tig.2007.11.010
Critical events of oogenesis occur during three distinct developmental stages: meiotic initiation in the fetal ovary, follicle formation in the perinatal period, and oocyte growth and maturation in the adult. Evidence from studies in humans and mice suggests that the genetic quality of the egg may be influenced by events at each of these stages. Recent experimental studies add additional complexity, suggesting that environmental influences might adversely affect all three stages. Thus, understanding the molecular control of oogenesis during these critical developmental windows will not only contribute to an understanding of human aneuploidy, but also provide a means of assessing potential effects of environmental exposures on human reproductive health.
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- "Increasing rates of infertility in developed countries represent a major challenge to reproductive health. In many cases, this is related to a delay in female childbearing, whose oocyte number and quality declines dramatically with age, the so-called maternal age effect (Hunt and Hassold 2008; Nagaoka et al. 2012). The generation of aneuploid oocytes undermines the capacity to achieve pregnancy, leading to miscarriages or congenital abnormalities in the newborn (Hassold and Hunt 2001; Munné 2005; Nagaoka et al. 2012). "
ABSTRACT: Telomeres protect against genome instability and participate in chromosomal movements during gametogenesis, especially in meiosis. Thus, maintaining telomere structure and telomeric length is essential to both cell integrity and the production of germ cells. As a result, alteration of telomere homeostasis in the germ line may result in the generation of aneuploid gametes or gametogenesis disruption, triggering fertility problems. In this work, we provide an overview on fundamental aspects of the literature regarding the organization of telomeres in mammalian germ cells, paying special attention to telomere structure and function, as well as the maintenance of telomeric length during gametogenesis. Moreover, we discuss the different roles recently described for telomerase and TERRA in maintaining telomere functionality. Finally, we review how new findings in the field of reproductive biology underscore the role of telomere homeostasis as a potential biomarker for infertility. Overall, we anticipate that the study of telomere stability and equilibrium will contribute to improve diagnoses of patients; assess the risk of infertility in the offspring; and in turn, find new treatments.
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- "During adult human life, about 400 oocytes eventually reach maturation and are ovulated, finally leading to menopause [Baird et al. 2005; Faddy et al. 1992; Kaipia and Hsueh 1997]. As primordial follicles are arrested at dictyotene stage of meiosis for many years, the follicles during this long waiting period undergo degenerative change which is due to the action of environmental factors that can damage DNA [Baird et al. 2005; Eichenlaub-Ritter 2012; Hunt and Hassold 2008; Tarin 1996]. These degenerative changes which include DNA double strand breaks (DSBs) due to oxidative stress and other causative agents over time have been hypothesized to be a cause of ovarian aging and oocyte loss [Aitken 2014; Kurus et al. 2013; Titus et al. 2013]. "
ABSTRACT: Age related decline in reproductive performance in women is well documented and apoptosis has been considered as one of the reasons for the decline of primordial follicle reserve. Recently we observed a decline in the efficiency of DNA repair ability in aged rat primordial follicles as demonstrated by decreased mRNA levels of DNA repair genes BRCA1 and H2AX. In the present study, a two-dimensional electrophoresis (2DE) proteomic approach was employed to identify differentially expressed proteins in primordial follicles isolated from ovaries of immature (∼20 days) and aged (∼400-450 days) rats. Using MALDI-TOF/TOF MS, we identified 13 differentially expressed proteins (p < 0.05) which included seven up-regulated and six down-regulated proteins in aged primordial follicles. These proteins are involved in a wide range of biological functions including apoptosis, DNA repair, and the immune system. Interestingly, the differentially expressed proteins such as FIGNL1 (DNA repair) and BOK (apoptotic protein) have not been previously reported in the rat primordial follicles and these proteins can be related to some common features of ovarian aging such as loss of follicle reserve and genome integrity. The quantitative differences of two important proteins BOK and FIGNL1 observed by the proteomic analysis were correlated with the transcript levels, as determined by semi-quantitative RT-PCR. Our results improve the current knowledge about protein factors associated with molecular changes in rat primordial follicles as a function of aging and our understanding of the proteomic processes involved in degenerative changes observed in aging primordial follicles.
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- "This process requires precise control of homologous chromosome pairing and genetic recombination to secure accurate chromosome segregation and transferring of genetic materials to the next generation. Therefore, defects in meiotic progression cause aneuploidy, which leads to reproductive failure and congenital birth defects as evidenced by 7–10% of chromosomally abnormal pregnancies in humans (Hunt and Hassold 2008). Although a higher frequency of deleterious consequences arise from meiotic defects, relatively fewer studies have focused on the mechanisms underlying accurate meiotic rather than mitotic cell divisions, especially in multicellular systems. "
ABSTRACT: Although a growing number of studies have reported the importance of SUMOylation in genome maintenance and DNA double-strand break repair (DSBR), relevant target proteins and how this modification regulates their functions are yet to be clarified. Here, we analyzed SUMOylation of ZTF-8, the homolog of mammalian RHINO, to test the functional significance of this protein modification in the DSBR and DNA damage response (DDR) pathways in the Caenorhabditis elegans germline. We found that ZTF-8 is a direct target for SUMOylation in vivo and that its modification is required for DNA damage checkpoint induced apoptosis and DSBR. Non-SUMOylatable mutants of ZTF-8 mimic the phenotypes observed in ztf-8 null mutants including reduced fertility, impaired DNA damage repair and defective DNA damage checkpoint activation. However, while mutants for components acting in the SUMOylation pathway fail to properly localize ZTF-8, its localization is not altered in the ZTF-8 non-SUMOylatable mutants. Taken together, these data show that direct SUMOylation of ZTF-8 is required for its function in DSBR as well as DDR but not its localization. ZTF-8's human ortholog is enriched in the germline, but its meiotic role as well as its post-translational modification has never been explored. Therefore, our discovery may assist in understanding the regulatory mechanism of this protein in DSBR and DDR in the germline. Copyright © 2015, The Genetics Society of America.