Mol. Hum. Reprod. Advance Access originally published online on October 5, 2005
Molecular Human Reproduction 2005 11(9):623-630; doi:10.1093/molehr/gah231
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Post-ovulatory aging of mouse oocytes leads to decreased MAD2 transcripts and increased frequencies of premature centromere separation and anaphase
1Department of Biology, STECH 257, 9201 University City Boulevard, Charlotte, NC 28223, USA and 2Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center, P.O.Box 33932, 1501 Kings Hwy, Shreveport, LA 71130, USA
1 To whom correspondence should be addressed at: Department of Biology, STECH 257, 9201 University City Boulevard, Charlotte, NC 28223, USA. E-mail: nsteuerw{at}email.uncc.edu or nury.steuerwald{at}embryos.net
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Abstract |
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Numerous cytological and biochemical alterations occur as mammalian oocytes age post-ovulation. Some of these changes can predispose cells to aneuploidy. The objective of this study was to test the hypothesis that the level of MAD2 spindle assembly checkpoint (SAC) transcripts decrease as mouse oocytes age post-ovulation and that this decrease was associated with chromosome missegregation. Female Institute of Cancer Research (ICR) mice were superovulated and oocytes collected at 14 h, 19 h and 24 h post-HCG for cytogenetic and quantitative real-time rapid cycle fluorescent RT–PCR analyses. Premature centromere separation (PCS) is now generally recognized as a predisposition to aneuploidy. The data showed that the frequencies of PCS-incomplete (PCS-I) did not significantly (P > 0.05) increase with time post-ovulation; whereas the proportions of oocytes displaying PCS-complete (PCS-C) and premature anaphase (PA) were significantly (P < 0.01) greater at 19 h and 24 h post-HCG, respectively. The higher frequencies of PCS-C and PA found at 19 h and 24 h coincided with decreased levels of MAD2 transcripts at these same times. Although the decline in MAD 2 transcripts with oocyte aging represents only one of many potential mechanisms responsible for aneuploidy, a compromised SAC appears to have a role in the unfavourable reproductive outcome associated with post-ovulatory aged oocytes.
Key words: checkpoint genes/cytogenetics/gene expression/meiosis/oocyte
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Introduction |
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Although progress is being made in understanding the molecular mechanisms underlying chromosome segregation during mitosis, little is known about the numerous potential mechanisms of aneuploidy in mammalian germ cells. Accurate chromosome segregation requires a temporally coordinated interaction among protein kinases and phosphatases, microtubules, motor proteins, centrosomes, kinetochores and their associated proteins, spindle checkpoint proteins, anaphase promoting complex (APC), proteasomes and the securin-cohesion complex (Nasmyth, 2001
, 
002). Abnormal function or temporal disarray among the biochemical reactions and cellular organelles responsible for chromosome segregation have the potential for predisposing cells to aneuploidy.
Aneuploidy represents the greatest genetic burden of man. Approximately 10% of human embryos, 40–60% of early spontaneous abortuses and 0.31% of human newborns have an abnormal number of chromosomes that originated in parental germ cells (Bond and Chandley, 1983; Hook, 1985; Hecht and Hecht, 1987). Although numerous hypotheses have been proposed for describing the etiology of human aneuploidy, the only consistent findings remain its positive correlation with maternal age (Bond and Chandley, 1983; Hook, 1985; Chandley, 1987) and its more frequent occurrence during female meiosis I for particular chromosomes (Hassold, 1985; Hassold and Sherman, 1993).
In order for equal distribution of chromosomes to daughter cells during mitosis and meiosis II, the kinetochores of sister chromatids must attach amphitelically (sister kinetochores orientated to opposite poles of a bipolar spindle). This differs from meiosis I in that the two sister chromatids of each chromosome of a homologous pair must attach syntelically (both kinetochores of sister chromatids attached to a monastrol spindle), whereas each homologue attaches amphitelically to a bipolar spindle. To help insure accurate kinetochore–microtubule attachment and tension, cells rely on the spindle assembly checkpoint (SAC). This surveillance mechanism utilizes mitotic arrest deficient (MAD) and budding uninhibited by benomyl (BUB) proteins plus other components to delay anaphase and provide cells additional time for correcting defects (Musacchio and Hardwick, 2002; Bharadwal and Yu, 2004; Taylor et al., 2004). Any treatment or condition whereby proper kinetochore–microtubule tension and attachment are compromised can result in prolonged SAC activation. One example is that of the Eg5 mitotic kinesin inhibitor monastrol. This reversible, cell-permeable compound inhibits centrosome separation and retards SAC release in mammalian somatic cells (Kapoor et al., 2000) and induces monastral spindles and aneuploidy in mouse oocytes (Mailhes et al., 2004). Although the SAC acts as a safeguard for anaphase onset and chromosome segregation, it can be overridden even in the presence of abnormal spindle morphology, unattached kinetochores and faulty chromosome orientation (Rieder and Palazzo, 1992; Rieder et al., 1994). Thus, satisfying the SAC is not necessarily essential for continued cell viability and cell cycle progression.
Recognizing that additional data are needed, several potential fates have been ascribed to mitotic cells that have undergone prolonged metaphase arrest resulting from failure to satisfy the SAC. It seems that the ultimate destiny depends on: species, cell type, type of treatment (chemical, physical, etc.), time and duration of treatment during the cell cycle, dosage and whether or not a functional bipolar spindle is subsequently formed (Rieder and Maiato, 2004). If a functional spindle exists: (i) the cell may complete anaphase with an enhanced probability for chromosome missegregation, (ii) exit mitosis without cytokinesis (4N) and subsequently undergo mitoses with an increased risk of chromosome missegregation, (iii) exit mitosis without cytokinesis and either undergo cell death due to apoptosis or senescence following G1 arrest or (iv) undergo mitotic death via necrosis or apoptosis. Conversely, if a spindle is not formed, the SAC cannot be satisfied, and cells may undergo each of the four above events excluding the first possibility.
SAC proteins are present during mammalian oocyte meiosis. Phosphorylated BUB1 protein was detected at kinetochores during both metaphases I and II in mouse oocytes (Brunet et al., 2003). MAD1 SAC protein was also shown to be active in mouse oocytes (Zhang et al., 2005), and a functional MAD2-dependent checkpoint was identified during meiosis I in both mouse (Wassmann et al., 2003; Homer et al., 2005a) and rat (Zhang et al., 2004) oocytes. Recent results also showed that hMAD2 is present during meiosis I in human oocytes (Homer et al., 2005c). The importance of proper SAC function to chromosome segregation was highlighted by recent work showing that depletion of MAD2 increased the incidence of premature centromere separation (PCS) in human somatic cells (Michel et al., 2004) and of aneuploidy in both mouse mitotic cells (Dobles et al., 2000) and mouse oocytes (Homer et al., 2005b). Furthermore, depletion of BUB3 resulted in cytogenetic anomalies in mouse embryos (Kalitsis et al., 2000).
When the SAC is satisfied, the APC can be activated (Musacchio and Hardwick, 2002; Taylor et al., 2004). The APC represents a large protein complex that ubiquinates mitotic cyclins and other regulatory proteins that are destined for timely proteolysis by proteasomes (Kotani et al., 1999; Glickman and Ciechanover, 2002). Subsequent proteolysis of securin proteins by proteasomes enables the protease separase to inactivate the cohesion proteins that help hold chromosomes together (Jallepalli et al., 2001; Agarwal and Cohen-Fix, 2002; Uhlmann, 2003b).
In eukaryotes, chromosome cohesion is mediated by the multisubunit protein complex cohesion. Although highly conserved, cohesin’s subunit composition differs among species, mitosis and meiosis (Nasmyth, 2002). Most cohesion proteins are removed from mammalian chromosome arms during prophase and prometaphase, whereas a lesser amount is removed from kinetochores during anaphase (Lee and Orr-Weaver, 2001; Nasmyth, 2001, 2002). During meiosis I, centromeric cohesion between sister chromatids must be preserved to insure that they segregate to the same pole and later removed during meiosis II. During mammalian meiosis I, the meiosis-specific Rec8 cohesion protein co-exists with Scc1 complexes (Firooznia et al., 2005) and replaces Scc1 (Parisi et al., 1999; Watanabe and Nurse, 1999). Rec8 is needed to maintain sister centromere cohesion during meiosis I (Molnar et al., 1995; Klein et al., 1999). Rec8 mRNA has been found in mouse oocytes (Lee et al., 2002), and Rec8 can be cleaved by separase (Buonomo et al., 2000; Lee et al., 2002) which is needed for removing centromeric cohesin during anaphase onset in mouse oocytes (Herbert et al., 2003; Terret et al., 2003).
Precocious loss of cohesin proteins can lead to PCS of sister chromatids and homologues during both mitotic and meiotic divisions (Sonada et al., 2001; Hoque and Ishikawa, 2002; Uhlmann, 2003a). Ample data show that PCS represents a predisposition to chromosome missegregation (Angell, 1991; Soewarto et al., 1995; Dailey et al., 1996; Mailhes et al., 1997; Yin et al., 1998; Pellestor et al., 2002; Cupisti et al., 2003).
Although the underlying mechanisms have not been fully explored, there appears to be a relationship between MII oocyte aging, PCS and aneuploidy. Post-ovulatory oocyte aging involves a progressive diminution of the biochemical and physiologic processes that are essential for normal zygotic development (Wilcox et al., 1998; Liu and Keefe, 2002). Following ovulation or in vitro oocyte aging, there is a narrow window of time (12–24 h) available for optimal expression of mammalian oocyte development (Hafez, 1993). Although freshly ovulated and aged oocytes appear morphologically similar, they display numerous cellular organelle and biochemical differences. Some of these changes resemble those found following fertilization or parthenogenic activation (Tarin et al., 1996; Xu et al., 1997), whereas others involve alterations to the cellular organelles responsible for chromosome segregation.
Numerous studies have shown that in vivo and in vitro aging of mammalian MII oocytes is accompanied by various cytologic and biochemical alterations. These changes include fragmented female pronuclei (Fissore et al., 2002), chromosome displacement from the metaphase plate (Webb et al., 1986; Saito et al., 1993), meiotic spindle abnormalities (Eichenlaub-Ritter et al., 1986; Pickering et al., 1988; George et al., 1996; Kim et al., 1996), PCS (Rodman, 1971; Webb et al., 1986; Angell, 1991; Dailey et al., 1996) and zona pellucida and cortical granule changes alterations (Yanagimachi and Chang, 1961; Longo, 1981; Xu et al., 1997). In addition, polyploidy (Austin, 1967; Shaver and Carr, 1967; Vickers, 1969; Juetten and Bavister, 1983) and aneuploidy (Rodman, 1971; Yamamoto and Ingalls, 1972; Plachot et al., 1988; Sakurada et al., 1996; Mailhes et al., 1997, 1998) were reported in zygotes derived from aged oocytes.
Biochemical alterations involving kinase and phosphatase activities, protein synthesis and maternal mRNA recruitment have been also noted following oocyte aging. The lower levels of active maturation promoting factor (MPF) found in aged porcine (Kikuchi et al., 1995, 2000; Ma et al., 2005) and bovine (Liu et al., 1998) oocytes coupled with a diminished level of mitogen-activated protein kinases (MAPKs) in aged mouse (Xu et al., 1997) and porcine oocytes (Kikuchi et al., 2000; Ma et al., 2005) are believed to help initiate spontaneous oocyte activation. Interestingly, the levels of both active and inactive MPF could be regulated by exposing porcine oocytes to phosphatase and kinase inhibitors (Kikuchi et al., 2000). Such exogenous manipulation of MPF phosphorylation–dephosphorylation events may offer insight for controlling certain aspects of oocyte aging. Additionally, decreased levels of the c-mos protooncogene Mos were found in aged bovine oocytes (Wu et al., 1997), and reduced expression of MAPKs, the oocyte antiapoptotic protein BCL2, and Mad2 occurred following in vitro aging of porcine oocyte (Ma et al., 2005). We also point out that degradation of both MAD2 and BUB1 oocyte transcripts was correlated with maternal age in humans (Steuerwald et al., 2001).
Decreased SAC protein activity can lead to abnormal chromosome segregation. Partial down-regulation of either Mad1 or Mad2 resulted in SAC inactivation and subsequent aneuploidy in human HCT116 cells (Kienitz et al., 2005). The adenomatous polyposis coli (apc) tumor suppressor gene appears to have a role in chromosome segregation in that apc mutants exhibited defects involving spindle–kinetochore interactions and chromosome segregation (Fodde et al., 2001; Kaplan et al., 2001). Products of the apc form a complex with BUB1 and BUB3, localize to kinetochores during mitosis of mouse embryonic stem cells and enhance microtubule stability in vivo and in vitro (Zumbrunn et al., 2001). It was found that compound mutant mice (BubR1+/– ApcMin/+) displayed PCS and chromosomal instability (Rao et al., 2005), whereas disruption of the mouse BUB3 SAC gene resulted in chromosome anomalies and embryonic lethality (Kalitsis et al., 2000).
The above findings suggest that the increased incidence of PCS and aneuploidy noted in post-ovulatory aged oocytes may reflect a time-dependent attenuation in SAC efficacy. The objective of this study was to test the hypothesis that the level of MAD2 transcripts decline as oocytes age post-ovulation and is associated with cytogenetic alterations that predispose oocytes to aneuploidy.
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Materials and methods |
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Animals, hormones and chemical treatment
Virgin, female Institute of Cancer Research (ICR) (Harlan Sprague-Dawley) mice between 8 and 12 weeks of age (25–36 g body weight) were maintained under a 12 h light (0600–1800 h) and 12 h dark photoperiod with a room temperature between 21° and 23°C and relative humidity of 50 ± 5%. Teklad 22/5 rodent diet (W) 8640 (Harlan-Teklad, Winnfield, IA, USA) and water were provided ad libitum. This research was approved by the Louisiana State University Health Sciences Center Animal Resources Advisory Committee.
The number of maturing ovarian follicles was augmented by an i.p. injection of 5.0 IU pregnant mare’s serum (PMSG; National Hormone and Peptide Program, Dr. A.F. Parlow, Torrance, CA, USA). Ovulation was induced by an i.p. injection of 5.0 IU HCG (Sigma C1063, St. Louis, MO, USA) 48 h after PMSG.
Oocyte harvest and processing
Ovulated oocytes were collected 14, 19 and 24 h post-HCG and processed for cytogenetic analysis (Mailhes and Yuan, 1987). This procedure involves harvesting oocytes en masse from five to ten females during a 3-h period. Thus, for each treatment group, oocytes were harvested on multiple days.
Cytogenetic analysis and statistical analysis of data
When analysing mouse MII oocyte chromosomes for aneuploidy, it is essential to objectively distinguish between oocytes containing complete dyads (chromosomes) (Figure 1A) and those PCS cells containing single, unpaired chromatids. Such a distinction was attained by C-banding the chromosomes (Salamanca and Armendares, 1974); without C-banding a single chromatid (SC) may be mistakenly counted as a dyad, which has two chromatids. Oocytes categorized as PCS were portioned into two classifications (Mailhes et al., 2003): incomplete (PCS-I) contained both dyads and SCs (PCS-I, Figure 1B) and complete (PCS-C) contained only SCs (PCS-C, Figure 1C). Oocytes with two distinct groups of chromatids were classified as premature anaphase (PA, Figure 1D). In each MII oocyte analysed, the number of dyads and/or chromatids was counted at 1250x magnification to determine the frequency of aneuploidy. The number of hypoploid (n = 10–19
), haploid (n = 20), hyperploid (n = 20–29, Figure 1E) was recorded. MII oocytes containing SCs such as those with 20 dyads and one chromatid (n = 20, Figure 1F) were classified as hyperploid. The frequencies of each ploidy class were divided by the total number of MII cells analysed excluding diploidy. Because MI and diploid MII oocytes are not analysed for aneuploidy and are distinct categories, their frequencies were calculated relative to the total number of oocytes analysed. The number and type of structural chromosome aberrations were also recorded when present.
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For calculating aneuploidy, the frequencies of hyperploidy in the different experimental groups were used. This is a common practice because an unknown proportion of hypoploid cells is influenced by technical artifact resulting from excessive chromosome scatter when preparing slides. This does not imply that the hypoploidy data are unimportant; in fact, they are especially relevant for chromosome lagging events.
The following criteria were used for eliminating a cell from the analysis: inadequate C-banding to enable a distinction to be made between intact dyads and those separated at the centromere; overlapped or clumped chromosomes; or those with excessive chromosome scatter that precluded an objective analysis. Chi-square (two-tail) was used for the statistical analysis of cytogenetic data. Analysis of variance and linear regression were used for statistical analysis of MAD2 data.
Real-time fluorescence RT–PCR
Ovulated oocytes were collected at 14, 19 and 24 h post-HCG. Individual oocytes were washed through three successive drops of phosphate-buffered saline (PBS, Sigma) containing 0.1% polyvinylpyrrolidone (PVP, Sigma), collected in 1 µl of media and flash frozen at –80°C pending further analysis. Upon thaw, the oocytes were processed for RNA isolation, first-strand cDNA synthesis and quantitative RT–PCR as previously described (Steuerwald et al., 1999, 2000). Oligo primer analysis software (National Biosciences, Plymouth, MN, USA) was used for PCR primer design using sequences obtained from GenBank for mouse MAD2 (Accession number U83902
[GenBank]
). MAD2 primer sequences used were as follows: 5' GGTGGTGGTCATCTCAAAT and 3' TGTAGGCCACCATACTATTATTCA. PCR was performed using a Light-cyclerTM (Roche Applied Science, Indianapolis, IN, USA). Template from single oocytes was amplified by 40 cycles of denaturation for 0 s at 95°C, annealing of primers at 53°C (for MAD2) for 0 s and extension at 72°C for 15 s. An additional step was included in each PCR cycle to acquire fluorescence at approximately 3 degrees below the melting temperature of the specific product. The Light-cyclerTM quantification software was used to calculate the unknown concentrations by extrapolation to a standard curve of known concentrations.
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Results |
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The data in Table I summarize that the frequencies of PCS-C and PA were significantly (P < 0.01) higher in both the 19 and 24 h post-HCG groups relative to the 14 h group. These increases were associated with reduced levels of MAD2 transcripts at 19 and 24 h post-HCG (Table II). The differences among treatment groups in the frequencies of PCS-I, SC, hypohaploidy and hyperhaploidy were statistically nonsignificant (P > 0.05). MAD2 copy numbers obtained following real-time fluorescence RT–PCR analysis are presented in Table II. Analysis of variance (ANOVA) followed by Newman-Keuls multiple comparisons test revealed that the concentrations of MAD2 transcripts are significantly different (P < 0.05) at each time period examined. Regression analysis confirmed that a negative linear correlation exists between length of time post-HCG versus transcript copy number (Figure 2). The slope of the regression line was significantly different from zero (P < .001). However, no statistically significant association was noted between the concentration of ß-actin mRNA and time in culture (P > 0.05).
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Discussion |
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Previous results showed that as time post-ovulation increased, oocytes initially undergo PCS-I, then PCS-C, and later PA. Both PCS and PA predisposed MII oocytes to aneuploidy as detected in one-cell zygotes (Mailhes et al., 1998
). The present data (Table I) support this contention in that the frequencies of PCS-I did not significantly (P > 0.05) increase with time post-HCG, whereas the proportions of oocytes displaying PCS-C and PA were highest at 19 h and 24 h, respectively. A plausible explanation for the similar frequencies of PCS-I among groups is that at 14h post-HCG, the transition from PCS-I to PCS-C had already occurred. We reported earlier that 87.0% of ICR mouse oocytes were already in MII 10h post-HCG (Marchetti and Mailhes, 1994). The frequencies of SC, hypohaploidy and hyperhaploidy would not be expected to increase with time post-ovulation, because an intervening cell division is needed to detect such aberrations. Furthermore, considerable data have demonstrated that PCS represents a predisposition to aneuploidy (Angell, 1991; Soewarto et al., 1995; Dailey et al., 1996; Mailhes et al., 1997; Yin et al., 1998; Pellestor et al., 2002; Cupisti et al., 2003).
The significantly (P < 0.01) higher frequencies of PCS-C and PA found at 19h and 24h coincided with decreased levels of MAD2 transcripts at these same times. This finding is supported by recent data from both mouse and pig oocytes. As in vitro culture time increased, MAD-2 levels decreased, whereas the frequencies of cells with abnormal spindles and chromosome alignment increased (Ma et al., 2005). Also, data from Mad2 knockdown experiments during meiosis I of in vitro cultured mouse oocytes showed elevated levels of aneuploidy in MII oocytes (Homer et al., 2005a,b). Although recognizing that diminished SAC activity represents only one of many potential mechanisms that may lead to aneuploidy, the present data coupled with the above Mad2 knockdown experiments suggest that depletion of MAD2 checkpoint activity, either induced during meiosis I or resulting from post-ovulatory oocyte aging, can lead to PCS and subsequent aneuploidy. We conclude that compromised MAD2 activity during in vivo aging of ovulated mouse oocytes appears to be one of numerous potential mechanistic pathways responsible for chromosome missegregation.
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Acknowledgements |
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The authors thank Joel V. Bailey and Colette Mastromatteo for expert technical assistance.
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Submitted on June 23, 2005; revised on August 29, 2005; accepted on September 6, 2005
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