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: 11.6). 03/2008; 24(2):86-93. DOI: 10.1016/j.tig.2007.11.010
Source: PubMed

ABSTRACT 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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    • "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. "
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    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.
    Genetics 03/2015; 200(2). DOI:10.1534/genetics.115.175661 · 4.87 Impact Factor
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    • "To investigate the role of the Y centromere structure on chromosome stability we have used two spontaneous laboratory mouse mutant strains, BALB/cWt and A/HeJ, that are associated with a high incidence of hermaphroditism [9], [10]. Both mutant strains display high rates of Y chromosome non-disjunction when compared to inbred strains that carry their progenitor Y chromosome [11], [12], [13]. It has been hypothesized that mutations at or near the Y centromere may contribute to the chromosome instability phenotype [14]. "
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    ABSTRACT: The centromere is an essential chromosomal structure that is required for the faithful distribution of replicated chromosomes to daughter cells. Defects in the centromere can compromise the stability of chromosomes resulting in segregation errors. We have characterised the centromeric structure of the spontaneous mutant mouse strain, BALB/cWt, which exhibits a high rate of Y chromosome instability. The Y centromere DNA array shows a de novo interstitial deletion and a reduction in the level of the foundation centromere protein, CENP-A, when compared to the non-deleted centromere array in the progenitor strain. These results suggest there is a lower threshold limit of centromere size that ensures full kinetochore function during cell division.
    PLoS ONE 01/2014; 9(1):e86875. DOI:10.1371/journal.pone.0086875 · 3.23 Impact Factor
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    • "We examined the ovaries of the Wisp3+/GFP-Cre; ROSA26+/mTmG dams by fluorescence microscopy to look for evidence of Cre-mediated recombination in oocytes but found none (data not shown). Most oocytes in fertile female mice are arrested at the diplotene stage of prophase I [21,22]. Since that stage of oocyte arrest is later than the stage in meiosis in which Wisp3+/GFP-Cre-mediated recombination had already occurred in males, it appears as though Wisp3+/GFP-Cre expression commences later and less often during female meiosis compared to male meiosis. "
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    ABSTRACT: Individuals with the autosomal recessive skeletal disorder Progressive Pseudorheumatoid Dysplasia have loss-of-function mutations in WISP3, and aberrant WISP3 expression has been detected in tumors from patients with colon and breast cancer. In mice however, neither absence nor over-expression of WISP3 was found to cause a phenotype, and endogenous Wisp3 expression has been difficult to detect. To confirm that Wisp3 knockout mice have no phenotype and to identify potential sites of endogenous Wisp3 expression, we generated mice with a knockin allele (Wisp3 (GFP-Cre)) designed to express Green Fluorescent Protein (GFP) and Cre-recombinase instead of WISP3. Heterozygous and homozygous knockin mice were fertile and indistinguishable from their wild-type littermates, confirming that mice lacking Wisp3 have no phenotype. We could not detect GFP-expression from the knockin allele, but we could detect Cre-expression after crossing mice with the knockin allele to Cre-reporter mice; the double heterozygous offspring had evidence of Cre-mediated recombination in several tissues. The only tissue that had high levels of Cre-mediated recombination was the testis, where recombination in spermatocytes occurred by early prophase of meiosis I. As a consequence, males that were double heterozygous for a Wisp3 (GFP-Cre) and a floxed allele only contributed a recombined allele to their offspring. We detected no evidence of Cre-mediated recombination in the female ovary, although when double heterozygous females contributed the reporter allele to their offspring it had recombined ~7% of the time. Wisp3 (GFP-Cre) expression therefore occurs less frequently and most likely at a later stage of oocyte development in female mice compared to male mice. We conclude that although WISP3 is dispensable in mice, male mice with a Wisp3 (GFP-Cre) allele (Jackson Laboratory stock # 017685) will be useful for studying early prophase of meiosis I and for efficiently recombining floxed alleles that are passed to offspring.
    PLoS ONE 09/2013; 8(9):e75116. DOI:10.1371/journal.pone.0075116 · 3.23 Impact Factor
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