The horse as a natural model to study reproductive aging-induced aneuploidy and weakened centromeric cohesion in oocytes

Rizzo, Maria; Preez, Nikola du; Ducheyne, Kaatje; Deelen, C.; Beitsma, M.; Stout, T.A.E.; Ruijter-Villani, Marta de

doi:10.18632/aging.104159

Cited by 14 publications

(17 citation statements)

References 41 publications

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“…After nuclear envelope breakdown (NEBD), the microtubules start nucleating from the chromosomes, and γ-tubulin is only detectable on the minus ends of the microtubules as a diffuse staining at the spindle poles ( Li et al, 2006 , p. 661–667; Roeles and Tsiavaliaris, 2019 ). We recently showed that the age-related change in the incidence of aneuploidy in MII oocytes from mares (15% in young and 55% in old mares) is comparable to that reported for women (20% in women younger than 35 years; 60% in women older than 35 years) ( Chiang et al, 2010 , p. 1522–1528; Lister et al, 2010 , p. 1511–1521; Fragouli et al, 2011 , p. 286–295; Rizzo et al, 2020 , p. 22220–22232). Moreover, the mechanics of mis-segregation appear to be analogous, since the majority of aneuploidies observed in aged mare oocytes were the result of premature separation of sister chromatids ( Rizzo et al, 2020 ).…”

Section: Introductionsupporting

confidence: 53%

“…We recently showed that the age-related change in the incidence of aneuploidy in MII oocytes from mares (15% in young and 55% in old mares) is comparable to that reported for women (20% in women younger than 35 years; 60% in women older than 35 years) (Chiang et al, 2010(Chiang et al, , p. 1522(Chiang et al, -1528Lister et al, 2010Lister et al, , p. 1511Lister et al, -1521Fragouli et al, 2011, p. 286-295;Rizzo et al, 2020, p. 22220-22232). Moreover, the mechanics of mis-segregation appear to be analogous, since the majority of aneuploidies observed in aged mare oocytes were the result of premature separation of sister chromatids (Rizzo et al, 2020). The aim of the present study was to investigate the effects of advanced maternal age on MPS1 and AURKC gene expression, and examine whether function of these kinases plays an essential role in stabilizing spindle bipolarity in oocytes.…”

Section: Introductionmentioning

confidence: 97%

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Compromised MPS1 Activity Induces Multipolar Spindle Formation in Oocytes From Aged Mares: Establishing the Horse as a Natural Animal Model to Study Age-Induced Oocyte Meiotic Spindle Instability

Rizzo

Stout

Cristarella

et al. 2021

Front. Cell Dev. Biol.

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Aneuploidy originating during meiosis in oocytes is the major cause of reduced fertility, implantation failure and miscarriage in women beyond their mid-thirties. Loss of chromosome cohesion, and defective microtubule dynamics and spindle assembly are, in turn, the major contributors to the error-prone nature of chromosome segregation in the oocytes of older women. However, the underlying molecular defects are not well understood. Altered function of MPS1 and AURKC have been shown to induce multipolar spindle phenotypes in murine oocytes and cancer cells, however, their role in reproductive aging associated oocyte aneuploidy is not known. Although age-related gamete and embryonic aneuploidy has been studied in female rodents, the horse may be a more appropriate animal model. Similar to women, aged mares suffer from reduced fertility and an increased incidence of oocyte aneuploidy. Moreover, mares show a long interval (decades) to reproductive senescence and, unlike rodents but similar to women, horse oocytes assemble the meiotic spindle in a slow and unstable manner, independent of microtubule organizing centers. In this study we found that oocytes from aged mares have lower expression of mRNA for Mps1, Spc25 and AurkC than oocytes from young mares while gene expression for other meiosis regulators did not differ. To assess the ability of horse oocytes to correctly form a bipolar spindle, in vitro matured MII oocytes were allowed to re-form their spindle after nocodazole-induced microtubule depolymerization. To investigate the importance of MPS1 and AURKC function in spindle (re)assembly, various concentrations of a MPS1 inhibitor (MPS1i, Compound 5) or an AURK inhibitor (AURKi, ZM447439) were included after nocodazole washout. MII oocytes from aged mares showed a higher incidence of spindle abnormalities after exposure to MPS1i. In contrast, Aurora kinase inhibition severely impaired microtubule organization and spindle formation in all oocytes, irrespective of mare age. In conclusion, gene expression for the kinases Mps1, Spc25, and AurkC is reduced in oocytes from aged mares. Moreover, spindle (re)assembly in aged mares’ oocytes is more unstable when Mps1 is inhibited. Overall, this suggests that compromised Mps1 activity predisposes to meiotic spindle instability in aged mare oocytes. This spindle instability could predispose to chromosome segregation errors.

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Section: Introductionsupporting

confidence: 53%

Section: Introductionmentioning

confidence: 97%

Compromised MPS1 Activity Induces Multipolar Spindle Formation in Oocytes From Aged Mares: Establishing the Horse as a Natural Animal Model to Study Age-Induced Oocyte Meiotic Spindle Instability

Rizzo

Stout

Cristarella

et al. 2021

Front. Cell Dev. Biol.

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“…In cumulus-oocytes complexes, moreover, maternal age alters the expression of 48 genes identified in humans to be related to maternal aging and aneuploidy, which may be associated to the reduced developmental competence observed in old mares' oocytes (Cox et al 2015). After in vitro maturation (IVM), predisposition to chromosome misalignment on the metaphase II spindle have been observed in oocytes from old mares (Rizzo et al 2019), possibly linked to a weakened centromeric cohesion of spindle (Rizzo et al 2020), as confirmed by the reduced expression of Mono Polar Spindle 1 kinase (MPS1) in IVM oocytes from old mares leading to meiotic spindle instability, which could in return predispose to poorer chromosome segregation (Rizzo et al 2021). Loss of cohesion and poor spindle stability induce premature and poor separation of sister chromatids during the end of the first meiotic division, conducive to embryonic aneuploidy (Rizzo et al 2019(Rizzo et al , 2020(Rizzo et al , 2021.…”

Section: Oocyte Qualitymentioning

confidence: 99%

Female age and parity in horses: how and why does it matter?

Derisoud

Auclair-Ronzaud

Palmer

et al. 2021

Reprod. Fertil. Dev.

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Although puberty can occur as early as 14–15months of age, depending on breed and use, the reproductive career of mares may continue to advanced ages. Once mares are used as broodmares, they will usually produce foals once a year until they become unfertile, and their productivity can be enhanced and/or prolonged through embryo technologies. There is a general consensus that old mares are less fertile, but maternal age and parity are confounding factors because nulliparous mares are usually younger and older mares are multiparous in most studies. This review shows that age critically affects cyclicity, folliculogenesis, oocyte and embryo quality as well as presence of oviductal masses and uterine tract function. Maternal parity has a non-linear effect. Primiparity has a major influence on placental and foal development, with smaller foals at the first gestation that remain smaller postnatally. After the first gestation, endometrial quality and uterine clearance capacities decline progressively with increasing parity and age, whilst placental and foal birthweight and milk production increase. These combined effects should be carefully balanced when breeding mares, in particular when choosing and caring for recipients and their foals.

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“…Alterations of the expression of several genes have been also observed during in vivo and in vitro oocyte maturation 16,17 . Moreover, after in vitro maturation, higher spindle instability is observed in old versus young mares' oocytes, resulting in increased risks of chromosome misalignment leading to embryo aneuploidy [18][19][20] . Controversial effects of mare age on mitochondria degeneration have been also reported 16,[21][22][23] .…”

Section: Introductionmentioning

confidence: 99%

Maternal age affects equine Day 8 embryo gene expression both in trophoblast and inner cell mass

Derisoud

Jouneau

Dubois³

et al. 2021

Preprint

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Background: Increased embryo loss as mares become older is a major consideration for breeders as older animals are currently used for reproduction in the equine industry. Lower embryo quality has been pointed out as partly responsible for this reduced fertility. Here, the effect of mare's age on blastocysts' gene expression was explored. Day 8 post ovulation embryos were collected by uterine flushing from multiparous young (YM, 6-year-old, N = 5) and older (OM, > 10-year-old, N = 6) non-nursing Saddlebred mares, inseminated with the semen of one stallion. Pure (TE_part) or inner cell mass enriched (ICMandTE) trophoblast were obtained by embryo bisection and paired end, non-oriented RNA sequencing (Illumina, NextSeq500) was performed on each hemi-embryo. To discriminate gene expression in the ICM from that in the TE, deconvolution (DeMixT R package) was used on the ICMandTE dataset. Differential expression was analyzed (DESeq2) with embryo sex and diameter as cofactors using a false discovery rate < 0.05 cutoff. Functional annotation and classification of differentially expressed genes and gene set enrichment analysis were also performed. Results: Maternal aging did not affect embryo recovery rate, embryo diameter nor total RNA quantity but modified gene expression in equine D8 embryos. The expression of genes in the ICM seemed to be more altered by maternal aging than in the TE. In both compartments, the expression of genes involved in mitochondrial function, translation and transcription due to chromatin modification were disturbed by maternal age. Mitosis, signaling and adhesion pathways and embryo development were particularly decreased in the ICM hemi-embryos from old mares. Finally, in TE, ion movement related genes were affected. Conclusions: This is the first study showing an effect of maternal age on gene expression in the equine blastocyst at Day 8 post ovulation. Maternal age, even for mares as young as 10 years old, disturbs mitosis, translation and transcription, cell signaling and adhesion as well as mitochondrial function and cell commitment of horse embryos. These perturbations may affect further embryo development and contribute to decreased fertility due to aging.

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The horse as a natural model to study reproductive aging-induced aneuploidy and weakened centromeric cohesion in oocytes

Cited by 14 publications

References 41 publications

Compromised MPS1 Activity Induces Multipolar Spindle Formation in Oocytes From Aged Mares: Establishing the Horse as a Natural Animal Model to Study Age-Induced Oocyte Meiotic Spindle Instability

Compromised MPS1 Activity Induces Multipolar Spindle Formation in Oocytes From Aged Mares: Establishing the Horse as a Natural Animal Model to Study Age-Induced Oocyte Meiotic Spindle Instability

Female age and parity in horses: how and why does it matter?

Maternal age affects equine Day 8 embryo gene expression both in trophoblast and inner cell mass

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