Human female meiosis: what makes a good egg go bad?

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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    ABSTRACT: Down syndrome represents the most frequent live born aneuploidy and genetic form of intellectual disability. The overwhelming majority of live born Down syndrome is caused by trisomy 21 condition, although a small fraction is due to the inheritance of de novo translocated chromosome 21. The extra copy of chromosome 21 originates owing to non-separation or nondisjunction of chromosome at anaphase in meiotic cell division of gametogenesis. Sincere research attempt have recognized that the higher incidence of Down syndrome birth is associated with maternal advanced age of conception and reduced recombination on chromosome 21. Using panel of short tandem repeat (STR) markers scientists have proved for overwhelming majority of cases, the error originates in maternal first meiotic division when the oocyte grows in fetal ovary and the maternal age effect is restricted only to these maternally originated cases. Several hypotheses have been proposed to explain this maternal age associated increase in the incidence of Down syndrome birth. With large population sample and refined analytical approaches scientists have determined that the effect of recombination error on the nondisjunction is bimodal. On one hand, overall reduction in recombination frequency imparts a risk of nondisjunction irrespective of maternal age. On other hand, some susceptible chiasma configurations increase the chance of chromosome malsegregation with advancing maternal age. Thus the risk factors for the chromosome 21 nondisjunction are of two categories namely, maternal age independent and maternal age dependent. Beside these, some genetic polymorphisms show high degree of susceptibility for Down syndrome conception among women. The gene MTHFR is such candidate which is actually involved in folic acid metabolism pathway and its specific polymorphisms exhibits predisposition to missegregation of Ch21 irrespective of ethnicity of population across the globe. The present review is focused to address the latest development in understanding the role of genetic and molecular risk factors for Down syndrome birth. Keywords: Down syndrome; Nondisjunction; Maternal Age; Recombination; Genetic polymorphism
    Journal of Cell Science & Molecular Biology. 11/2014; 1(2):1-9.
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    ABSTRACT: OBJECTIVE: To study whether the telomere structure of germ cells from idiopathic infertile men is altered and if this impairment is influenced by meiotic recombination and telomere length. DESIGN: We performed a detailed analysis of both telomeric repeat-containing RNA (TERRA) and telomerase distribution in testis cell spreads by combining immunofluorescence and RNA fluorescent in situ hybridization. In addition we analyzed meiotic recombination between homologous chromosomes by immunofluorescence and telomere length by quantitative fluorescent in situ hybridization. SETTING: University. PATIENT(S): Men consulting for fertility problems. INTERVENTION(S): Unilateral testicular biopsies. MAIN OUTCOME MEASURE(S): We observed that TERRA levels and its nuclear distribution were compromised in infertile patients. In addition, the presence of the protein component of telomerase at telomeres decreased in the affected patients. However, neither telomerase-TERRA association nor telomere length was altered in spermatocytes I of infertile samples compared with control individuals. In addition, we observed that meiotic recombination was reduced in infertile individuals. RESULT(S): Telomere homeostasis is impaired in infertile patients, and this was translated into a decrease in TERRA levels together with an alteration of the TERRA-protein component of telomerase telomeric association in primary spermatocytes. CONCLUSION(S): This study demonstrates for the first time that telomere structure and homeostasis in germ cells is compromised in infertile individuals. In the light of our results we propose that the analysis of telomeric structure (i.e., TERRA levels and telomere association with TERRA and telomerase) would provide new tools for our understanding of the origin of human infertility.
    Fertility and Sterility 07/2014; · 4.30 Impact Factor
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    ABSTRACT: Chromosome segregation errors in human oocytes are the leading cause of birth defects, and the risk of aneuploid pregnancy increases dramatically as women age. Accurate segregation demands that sister chromatid cohesion remain intact for decades in human oocytes, and gradual loss of the original cohesive linkages established in fetal oocytes is proposed to be a major cause of age-dependent segregation errors. Here we demonstrate that maintenance of meiotic cohesion in Drosophila oocytes during prophase I requires an active rejuvenation program, and provide mechanistic insight into the molecular events that underlie rejuvenation. Gal4/UAS inducible knockdown of the cohesion establishment factor Eco after meiotic S phase, but before oocyte maturation, causes premature loss of meiotic cohesion, resulting in destabilization of chiasmata and subsequent missegregation of recombinant homologs. Reduction of individual cohesin subunits or the cohesin loader Nipped B during prophase I leads to similar defects. These data indicate that loading of newly synthesized replacement cohesin rings by Nipped B and establishment of new cohesive linkages by the acetyltransferase Eco must occur during prophase I to maintain cohesion in oocytes. Moreover, we show that rejuvenation of meiotic cohesion does not depend on the programmed induction of meiotic double strand breaks that occurs during early prophase I, and is therefore mechanistically distinct from the DNA damage cohesion re-establishment pathway identified in G2 vegetative yeast cells. Our work provides the first evidence that new cohesive linkages are established in Drosophila oocytes after meiotic S phase, and that these are required for accurate chromosome segregation. If such a pathway also operates in human oocytes, meiotic cohesion defects may become pronounced in a woman's thirties, not because the original cohesive linkages finally give out, but because the rejuvenation program can no longer supply new cohesive linkages at the same rate at which they are lost.
    PLoS Genetics 09/2014; 10(9):e1004607. · 8.17 Impact Factor


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