Vogt, E., Kirsch-Volders, M., Parry, J. & Eichenlaub-Ritter, U. Spindle formation, chromosome segregation and the spindle checkpoint in mammalian oocytes and susceptibility to meiotic error. Mutat. Res. 651, 14-29
The spindle assembly checkpoint (SAC) monitors attachment to microtubules and tension on chromosomes in mitosis and meiosis. It represents a surveillance mechanism that halts cells in M-phase in the presence of unattached chromosomes, associated with accumulation of checkpoint components, in particular, Mad2, at the kinetochores. A complex between the anaphase promoting factor/cylosome (APC/C), its accessory protein Cdc20 and proteins of the SAC renders APC/C inactive, usually until all chromosomes are properly assembled at the spindle equator (chromosome congression) and under tension from spindle fibres. Upon release from the SAC the APC/C can target proteins like cyclin B and securin for degradation by the proteasome. Securin degradation causes activation of separase proteolytic enzyme, and in mitosis cleavage of cohesin proteins at the centromeres and arms of sister chromatids. In meiosis I only the cohesin proteins at the sister chromatid arms are cleaved. This requires meiosis specific components and tight regulation by kinase and phosphatase activities. There is no S-phase between meiotic divisions. Second meiosis resembles mitosis. Mammalian oocytes arrest constitutively at metaphase II in presence of aligned chromosomes, which is due to the activity of the cytostatic factor (CSF). The SAC has been identified in spermatogenesis and oogenesis, but gender-differences may contribute to sex-specific differential responses to aneugens. The age-related reduction in expression of components of the SAC in mammalian oocytes may act synergistically with spindle and other cell organelles' dysfunction, and a partial loss of cohesion between sister chromatids to predispose oocytes to errors in chromosome segregation. This might affect dose-response to aneugens. In view of the tendency to have children at advanced maternal ages it appears relevant to pursue studies on consequences of ageing on the susceptibility of human oocytes to the induction of meiotic error by aneugens and establish models to assess risks to human health by environmental exposures.
"It is interesting to note that the contribution of segregation defects to infertility differs between male and female house mice. Thus, data suggest that female meiosis is more prone to chromosome misalignment on the spindle, on the basis of the incidence of unbalanced gametes (Hunt and Hassold 2002; Vogt et al. 2008). This tendency in females may reflect the acentrosomal spindle in oocytes, a less stringent functioning of the spindle checkpoint and even differences in the process of sister chromatid cohesion release at first meiotic anaphase (Homer 2011; LeMaire-Adkins et al. 1997; Lister et al. 2010). "
[Show abstract][Hide abstract] ABSTRACT: Many different chromosomal races with reduced chromosome number due to the presence of Robertsonian fusion metacentrics have been described in western Europe and northern Africa, within the distribution area of the western house mouse Mus musculus domesticus. This subspecies of house mouse has become the ideal model for studies to elucidate the processes of chromosome mutation and fixation that lead to the formation of chromosomal races and for studies on the impact of chromosome heterozygosities on reproductive isolation and speciation. In this review, we briefly describe the history of the discovery of the first and subsequent metacentric races in house mice; then, we focus on the molecular composition of the centromeric regions involved in chromosome fusion to examine the molecular characteristics that may explain the great variability of the karyotype that house mice show. The influence that metacentrics exert on the nuclear architecture of the male meiocytes and the consequences on meiotic progression are described to illustrate the impact that chromosomal heterozygosities exert on fertility of house mice-of relevance to reproductive isolation and speciation. The evolutionary significance of the Robertsonian phenomenon in the house mouse is discussed in the final section of this review.
"It has been reported that maternal aging can dramatically influence the meiotic spindle assembly process in mammals [29-34], leading to spindle disorganization and chromosome segregation errors, which in turn cause aneuploid formation. In addition, the deterioration of sister chromatid cohesion [35-40] and failure of the spindle assembly checkpoint [41-44] in the oocytes are also crucial reasons for aneuploid formation. "
[Show abstract][Hide abstract] ABSTRACT: Background
Aneuploidy is one of the major factors that result in low efficiency in human infertility treatment by in vitro fertilization (IVF). The development of DNA microarray technology allows for aneuploidy screening by analyzing all 23 pairs of chromosomes in human embryos. All chromosome screening for aneuploidy is more accurate than partial chromosome screening, as errors can occur in any chromosome. Currently, chromosome screening for aneuploidy is performed in developing embryos, mainly blastocysts. It has not been performed in arrested embryos and/or compared between developing embryos and arrested embryos from the same IVF cycle.
The present study was designed to examine all chromosomes in blastocysts and arrested embryos from the same cycle in patients of advanced maternal ages. Embryos were produced by routine IVF procedures. A total of 90 embryos (45 blastocysts and 45 arrested embryos) from 17 patients were biopsied and analyzed by the Agilent DNA array platform.
It was found that 50% of the embryos developed to blastocyst stage; however, only 15.6% of the embryos (both blastocyst and arrested) were euploid, and most (84.4%) of the embryos had chromosomal abnormalities. Further analysis indicated that 28.9% of blastocysts were euploid and 71.1% were aneuploid. By contrast, only one (2.2%) arrested embryo was euploid while others (97.8%) were aneuploid. The prevalence of multiple chromosomal abnormalities in the aneuploid embryos was also higher in the arrested embryos than in the blastocysts.
These results indicate that high proportions of human embryos from patients of advanced maternal age are aneuploid, and the arrested embryos are more likely to have abnormal chromosomes than developing embryos.
Journal of Ovarian Research 06/2014; 7(1):65. DOI:10.1186/1757-2215-7-65 · 2.43 Impact Factor
"This suggests that STK31 might play an important role in the regulation of cell cycle progression during male germ cell development. In gametogenesis, mechanisms sensing abnormalities and checkpoint controls are critical for preventing aneuploidy in the embryo derived by aneuploid sperm and oocytes, which is the leading cause of spontaneous abortions and pregnancy loss in human . Further studies are needed to explore the role of STK31 in human reproduction. "
[Show abstract][Hide abstract] ABSTRACT: Serine/threonine kinase 31 (STK31) is one of the novel cancer/testis antigens for which its biological functions remain largely unclear. Here, we demonstrate that STK31 is overexpressed in many human colorectal cancer cell lines and tissues. STK31 co-localizes with pericentrin in the centrosomal region throughout all phases of the cell cycle. Interestingly, when cells undergo mitosis, STK31 also localizes to the centromeres, central spindle, and midbody. This localization behavior is similar to that of chromosomal passenger proteins, which are known to be the important players of the spindle assembly checkpoint. The expression of STK31 is cell cycle-dependent through the regulation of a putative D-box near its C-terminal region. Ectopically-expressed STK31-GFP increases cell migration and invasive ability without altering the proliferation rate of cancer cells, whereas the knockdown expression of endogenous STK31 by lentivirus-derived shRNA results in microtubule assembly defects that prolong the duration of mitosis and lead to apoptosis. Taken together, our results suggest that the aberrant expression of STK31 contributes to tumorigenicity in somatic cancer cells. STK31 might therefore act as a potential therapeutic target in human somatic cancers.
PLoS ONE 03/2014; 9(3):e93303. DOI:10.1371/journal.pone.0093303 · 3.23 Impact Factor
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