Microtubule dynamics and age-related aneuploidy in mammalian oocytes

在受精过程中，精子和卵子的融合产生了一个新的个体，每一个都为后代贡献了一半的遗传物质（染色体）。然而，由于人们知之甚少的原因，卵子的发育容易出错，例如未受精卵经常拥有错误数量的染色体。随着女性年龄的增长，这种情况尤其明显。这些染色体异常（“非整倍体”）的卵子是导致唐氏症等发育状况的原因，是流产（意外流产）的主要原因，也是与年龄有关的不孕不育的主要原因。在这个项目中，我们将研究卵子非整倍性的原因，特别关注纺锤体，在卵子发育的最后细胞分裂过程中，细胞的一部分负责确保染色体在细胞之间正确分裂（称为染色体分离）。我们使用最先进的显微镜检查纺锤体功能的不同特征。我们将比较老年小鼠和年轻小鼠卵子中的纺锤体，以精确确定老年小鼠卵子中的纺锤体有什么不同，这使得它更容易发生染色体分离错误。我们的初步数据与一种观点是一致的，即一种被称为Kinesin-13s的蛋白质家族在确保染色体正确分离方面可能特别重要，并且在老卵子中可能存在缺陷。我们将使用多种方法直接测试驱动蛋白-13s在卵子发育中的作用，并确定哪些蛋白质对防止染色体分离错误最重要。特别是，我们将给老卵子提供额外的酪蛋白-13s，以直接防止染色体错误分离。这些实验是首次尝试防止卵子中与年龄相关的染色体错误分离。在与临床同事的合作中，我们将确定纺锤体操作是否也可以预防人类卵子的错误。我们的实验将提供关键信息，解释为什么发育中的卵子可能会出现染色体分离错误，特别是在老年母亲中，并可能提供原理证明，即染色体分离错误可以通过操纵纺锤体来预防，否则会导致疾病。

At fertilisation a new individual is created by the fusion of the sperm and the egg, each of which contributes half of the genetic material (chromosomes) for the offspring. However, for reasons which are very poorly understood, the development of the egg is error-prone, such that unfertilised eggs frequently possess the wrong number of chromosomes. This is particularly the case as women get older. These chromosomally abnormal ('aneuploid') eggs are the cause of developmental conditions such as Down's, are a leading cause of miscarriage (unwanted pregnancy loss), and are the leading reason for age-related infertility.In this project we will investigate the cause of aneuploidy in eggs, particularly focussing on the spindle, the part of the cell responsible for ensuring that chromosomes are correctly divided between cells (called chromosome segregation) during the final cell division which occurs as part of egg development. We use state-of-the-art microscopy to examine different features of spindle function. We will be comparing spindles in eggs from old mice and young mice, to determine precisely what is different about the spindle in the developing egg from older mothers, which makes it more prone to chromosome segregation errors.Our preliminary data are consistent with the idea that a family of proteins called Kinesin-13s may be particularly important in making sure chromosomes are segregated correctly, and may be defective in old eggs. We will directly test the role of kinesin-13s in developing eggs using a variety of approaches, and establish which of these proteins are the most important for preventing chromosome segregation-errors. In particular, we will provide old eggs with extra kinesin-13s in a direct attempt to prevent chromosome mis-segregation. These experiments are the first to attempt to prevent age-related chromosome mis-segregation in eggs. In collaboration with clinical colleagues, we will determine whether spindle manipulations can also prevent errors in human eggs.Our experiments will provide key information as to why developing eggs are likely to mis-segregate chromosomes, particularly in older mothers, and may provide proof-of-principle that chromosome segregation errors which would otherwise cause disorders can be prevented by manipulating the spindle.