Does an aged egg regain its youth after fertilisation?

老化的卵子受精后会恢复青春吗？

• 批准号: 2305411
• 金额: --
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2305411
• 关键词: Does; aged; egg; regain; its

Sexual reproduction depends on the transmission of exactly one copy of each chromosome by the male and female gamete during fertilisation. Gametes become haploid during a specialised cell division known as meiosis. Female meiosis is error prone and this increases markedly as women get older. As a consequence, there is a sharp decline in fertility and an increased risk of miscarriage and birth defects from the age of ~35 years. Taken together with the increased tendency for women to delay starting a family, female reproductive ageing is one of the most pressing problem for human reproductive health. Meiosis is a highly conserved process involving meiotic recombination between replicated parental homologues to from bivalent chromosomes, which are resolved to their four constituent chromatids during two successive meiotic divisions. This depends on stepwise removal of chromosomal cohesion: first from arms during meiosis I and then from centromeres during meiosis II. In females, meiosis occurs over an extraordinarily protracted period, commencing during fetal life and not completed until the mature egg is fertilised. Baby girls are born with their lifetime supply of primordial oocytes arrested in prophase of meiosis I. During the decades between being formed and recruited for growth and ovulation, primordial oocytes have the task of maintaining their nuclear and mitochondrial genomes in a pristine condition for transmission to the next generation. During this time bivalent chromosomes are stabilised by cohesin complexes containing the meiosis-specific subunit Rec8. We have previously found that female ageing is characterised by a marked reduction in oocyte chromosome-associated Rec8. Moreover, we found that this was associated with reduced recruitment of a protein known as Sgol2, which protects centromeric cohesin until the second meiotic division (Lister et al, 2010, Curr Biol). We also observed a marked age-related reduction in the level of kinetochore proteins recruited to oocyte centromeres. A primary goal of this project is to investigate the causes and consequences of age-related changes occurring at the centromere and to determine whether these are reset after the egg is fertilised. In addition, we will determine whether mitochondrial turnover reported to occur around the time of fertilisation also acts as a "resetting" mechanism to eliminate mtDNA mutations acquired during oogenesis. Experiments will be conducted in mouse and human oocytes. Broader implications of the project: The findings of the project will advance our understanding of the underlying causes female age-related infertility. In addition, the work has the potential to provide novel insights on the cell biology of ageing and mechanisms of regeneration. Experimental approach and training: Core techniques include super-resolution imaging of oocytes at all stages of development including after fertilisation. Making molecular tools for live cell imaging. Training will be provided in oocyte manipulation and micro-injection and 4D high resolution live cell imaging and advanced image analysis to study dynamic events in oocytes and early embryos. Next generation sequencing will be used for analysis of mitochondrial DNA.

有性生殖依赖于受精过程中雄性和雌性配子传递的每一条染色体的一个拷贝。配子在称为减数分裂的特殊细胞分裂过程中变成单倍体。女性减数分裂容易出错，而且随着年龄的增长，这种情况会明显增加。因此，生育率急剧下降，流产和出生缺陷的风险从35岁开始增加。再加上妇女推迟生育的趋势增加，女性生殖年龄老化是人类生殖健康最紧迫的问题之一。 减数分裂是一个高度保守的过程，涉及复制的亲本同源物之间的减数分裂重组，以形成二价染色体，这些染色体在两次连续的减数分裂期间被分解为它们的四个组成染色单体。这取决于逐步去除染色体的凝聚力：首先在减数分裂I期间从臂中去除，然后在减数分裂II期间从着丝粒中去除。在女性中，减数分裂发生在一个非常漫长的时期，从胎儿时期开始，直到成熟的卵子受精才完成。女婴出生时，其原始卵母细胞的终生供应被阻滞在减数分裂I的前期。在形成和招募生长和排卵之间的几十年中，原始卵母细胞的任务是将其核和线粒体基因组保持在原始状态，以便传递给下一代。在此期间，二价染色体稳定的凝聚素复合物含有减数分裂特异性亚基Rec8。我们以前发现，女性衰老的特点是显着减少卵母细胞染色体相关的Rec8。此外，我们发现这与称为Sgol 2的蛋白质的募集减少有关，Sgol 2保护着丝粒粘着蛋白直到第二次减数分裂（Lister等人，2010，Curr Biol）。我们还观察到一个显着的年龄相关的减少水平的着丝粒蛋白招募到卵母细胞着丝粒。该项目的主要目标是调查着丝粒发生的年龄相关变化的原因和后果，并确定这些变化是否在卵子受精后重置。此外，我们将确定是否线粒体周转报告发生在受精的时间也作为一个“重置”机制，以消除卵子发生过程中获得的mtDNA突变。实验将在小鼠和人卵母细胞中进行。 该项目的更广泛的影响：该项目的发现将促进我们对女性年龄相关不孕症的根本原因的理解。此外，这项工作有可能为衰老的细胞生物学和再生机制提供新的见解。 实验方法和培训：核心技术包括在受精后的所有发育阶段对卵母细胞进行超分辨率成像。制作活细胞成像的分子工具。将提供卵母细胞操作和显微注射以及4D高分辨率活细胞成像和高级图像分析方面的培训，以研究卵母细胞和早期胚胎中的动态事件。下一代测序将用于线粒体DNA的分析。