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Increased expression of BubR1 protects against aneuploidy in aging oocytes and extends reproductive lifespan

ABSTRACT: Chromosome aneuploidy increases in oocytes with maternal age, and is considered the leading cause for the increased incidence of infertility, miscarriage, and birth defects. Using mRNA-Sequencing of oocytes from 12 month old mouse versus 3 month young mouse, we identified a spindle assembly checkpoint gene, BubR1, whose expression was significantly decreased. We employed a mRNA microinjection based approach to increase BubR1 expression in aging oocytes. We find that increased expression of BubR1 protects against aneuploidy and chromosome misalignment in aging oocytes. After in vitro fertilization, the embryos derived from BubR1 increased expression aging oocytes exhibited chromosome stability as robust as those of the young ones. Furthermore, following embryo transfer, these embryos showed greatly improved developmental competency, with comparable levels of full-term development to those of the young ones. These results indicate that the decline in oocyte quality may be reversible and could lead to treatments that prolong female fertility.

ORGANISM(S): Mus musculus

PROVIDER: GSE57482 | GEO | 2014/05/10

SECONDARY ACCESSION(S): PRJNA246592

REPOSITORIES: GEO

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Increased expression of BubR1 protects against aneuploidy in aging oocytes and extends reproductive lifespan

Project description:Chromosome aneuploidy increases in oocytes with maternal age, and is considered the leading cause for the increased incidence of infertility, miscarriage, and birth defects. Using mRNA-Sequencing of oocytes from 12 month old mouse versus 3 month young mouse, we identified a spindle assembly checkpoint gene, BubR1, whose expression was significantly decreased. We employed a mRNA microinjection based approach to increase BubR1 expression in aging oocytes. We find that increased expression of BubR1 protects against aneuploidy and chromosome misalignment in aging oocytes. After in vitro fertilization, the embryos derived from BubR1 increased expression aging oocytes exhibited chromosome stability as robust as those of the young ones. Furthermore, following embryo transfer, these embryos showed greatly improved developmental competency, with comparable levels of full-term development to those of the young ones. These results indicate that the decline in oocyte quality may be reversible and could lead to treatments that prolong female fertility. Examination of the effect of maternal aging on the mRNA expression in the mature oocytes of the female mice. Naturally ovulated mature oocytes (MII stage) were collected from 6 young (3 month) and 6 aging (12 month) female mice (3 oocytes per mice, 18 oocytes for each group).

2014-05-10 | E-GEOD-57482 | biostudies-arrayexpress

Mus musculus

Project description:Increased expression of BubR1 protects against aneuploidy in aging oocytes and extends reproductive lifespan

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Granulosa cell mevalonate pathway abnormalities contribute to oocyte meiotic defects and aneuploidy [HiC GGOH-treatment]

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Transcription profiling of mouse oocytes to investigate age-associated increase in aneuploidy and changes in gene expression.

Project description:An increase in the incidence of aneuploidy is well documented with increasing maternal age, in particular in human females. Remarkably, little is known regarding the underlying molecular basis for the age-associated increase in aneuploidy, which is a major source of decreased fertility in humans. Using mouse as a model system we find that eggs obtained from old mice (60-70 weeks of age) display a 6-fold increase in the incidence of hyperploidy as assessed by chromosome spreads. Expression profiling of transcripts in oocytes and eggs obtained from young and old mice reveals that approximately 5% of the transcripts are differentially expressed in oocytes obtained from old females when compared to oocytes obtained from young females (6-12 weeks of age) and that this fraction increases to approximately 33% in eggs. The latter finding indicates that the normal pattern of degradation of maternal mRNAs that occurs during oocyte maturation is dramatically altered in eggs obtained from old mice and could therefore be a contributing source to the decline in fertility. Analysis of the differentially expressed transcripts also indicated that the strength of the spindle assembly checkpoint is weakened and that higher errors of microtubule-kinetochore interactions constitute part of molecular basis for the age-associated increase in aneuploidy in females. Last, BRCA1 expression is reduced in oocytes obtained from old females and RNAi-mediated reduction of BRCA1 in oocytes obtained from young females results in perturbing spindle formation and chromosome congression following maturation Experiment Overall Design: We profiled the global gene expression in GV & MII oocyte by maternal aging, and identified the genes differentially expressed.

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BubR1 allelic effects drive phenotypic heterogeneity in MVA progeria syndrome [3 month old RNA-seq]

Project description:Mosaic-variegated aneuploidy (MVA) syndrome is a rare childhood disorder characterized by biallelic BUBR1, CEP57, or TRIP13 aberrations, increased chromosome missegregation, and a broad spectrum of clinical features, including various cancers, congenital defects, and progeroid pathologies. To investigate the mechanisms underlying this disorder and its phenotypic heterogeneity, we mimicked the BUBR1L1012P mutation in mice (BubR1L1002P) and combined it with two other MVA variants, BUBR1X753 and BUBR1H, generating a truncated protein and low amounts of wildtype protein, respectively. Whereas, BubR1X753/L1002P and BubR1H/X753 mice die prematurely, BubR1H/L1002P mice are viable and exhibit many MVA features, including cancer predisposition and various progeroid phenotypes, including short lifespan, dwarfism, lipodystrophy, sarcopenia, and low cardiac stress tolerance. Strikingly, although these mice had a similar reduction in total BubR1 and spectrum of MVA phenotypes as BubR1H/H mice, several progeroid pathologies were attenuated in severity, which in skeletal muscle coincided with reduced senescence-associated secretory phenotype (SASP) complexity. Additionally, mice harboring heterozygous BUBR1 MVA variants developed mild MVA pathologies later in life, with alleles conferring unique phenotypic profiles. Together, these data demonstrate that subtle BUBR1 allelic effects contribute to disease heterogeneity in both MVA patients and heterozygous carriers of MVA mutations, independent of aneuploidy rates and BUBR1 protein levels.

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Project description:Chromosome segregation errors in oocytes lead to the production of aneuploid eggs, which are the leading cause of pregnancy loss and of several congenital diseases such as Down syndrome. The frequency of chromosome segregation errors in oocytes increases with maternal age, especially at a late stage of reproductive life. How aging at various life stages affects oocytes differently remains poorly understood. In this study, we describe aging-associated changes in the transcriptome profile of mouse oocytes throughout reproductive life. Our single-oocyte comprehensive RNA sequencing using RamDA-seq revealed that oocytes undergo transcriptome changes at a late reproductive stage, whereas their surrounding cumulus cells exhibit transcriptome changes at an earlier stage. Calorie restriction, a paradigm that reportedly prevents aging-associated egg aneuploidy, promotes a transcriptome shift in oocytes with the up-regulation of genes involved in chromosome segregation. This shift is accompanied by the improved maintenance of chromosomal cohesin, the loss of which is a hallmark of oocyte aging and causes chromosome segregation errors. These findings have implications for understanding how oocytes undergo aging-associated functional decline throughout their reproductive life in a context-dependent manner.

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Project description:The decline in oocyte quality is a limiting factor of female fertility; however, strategies to maintain the oocyte quality of aged women are not available. In this study, we showed that growth hormone (GH) supplementation in vivo not only alleviated the decline in oocyte number caused by aging, but also improved the quality and developmental potential of aged oocytes. Strikingly, GH supplementation reduced aneuploidy in aged oocytes. Proteomic analysis indicated that the ERK1/2 pathway was involved in the reduction in aneuploidy rate of aged oocytes, as confirmed both in vivo and in vitro. In addition, JAK2 might be involved in the regulation of ERK1/2 by GH in aged oocytes. Collectively, our findings revealed that GH supplementation protects oocytes from aging-related aneuploidy and enhances the quality of aged oocytes, and could be used to improve the outcome of assisted reproduction in aged women.

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