The causes and consequences of mitotic errors in embryonic stem cells

胚胎干细胞有丝分裂错误的原因和后果

• 批准号: 2594410
• 金额: --
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2594410
• 关键词: causes; consequences; mitotic; errors; embryonic

Mammalian development requires multiple, rapid cell divisions in order to support the growth and morphogenesis of the developing embryo. Given the limited number of early embryonic cells within the embryo that give rise to all cells in the adult body, errors occurring during cell division (mitotic errors) in these cells could have devastating consequences, from congenital defects to embryonic lethality. Yet, despite the pivotal importance of preserving genome integrity during early embryogenesis, embryonic cells are particularly prone to mitotic errors. Thus, fundamental unanswered questions in developmental biology are what makes embryonic cells susceptible to mitotic errors and how is robust development achieved against the backdrop of high rates of mitotic errors.Although early human embryogenesis is experimentally inaccessible, embryonic stem cell (ESC) lines can be derived from the inner cell mass of an early blastocyst. Therefore, ESCs represent a unique and powerful tool for studying otherwise intractable stages of development. We have recently demonstrated that the high frequency of mitotic errors characteristic of early embryos is also evident upon in vitro culture of ESCs (Zhang et al., 2019 Stem Cell Reports 12:557; Halliwell et al., 2020 Stem Cell Reports 14:1009), indicating that the susceptibility to mitotic errors is an intrinsic property of early embryonic cells and that ESC will provide a good platform for determining the A 2021-entry-WR-DTP-CASE-Form-A-Barbaric, Fellows Page 3 of 13mechanistic basis of these errors. The overall goal of this project is to elucidate molecular mechanisms governing a high incidence of mitotic errors in ESCsand to assess the impact of chromosome gains or losses (collectively known as aneuploidy) on the developmental potential of ESCs.

哺乳动物的发育需要多次快速的细胞分裂，以支持发育胚胎的生长和形态发生。鉴于胚胎中产生成人体内所有细胞的早期胚胎细胞数量有限，这些细胞在细胞分裂期间发生的错误（有丝分裂错误）可能会产生毁灭性的后果，从先天性缺陷到胚胎致死。然而，尽管在早期胚胎发生过程中保持基因组完整性至关重要，但胚胎细胞特别容易发生有丝分裂错误。因此，在发育生物学中，根本未回答的问题是什么使胚胎细胞易受有丝分裂错误的影响，以及如何在高有丝分裂错误率的背景下实现稳健的发育。虽然早期人类胚胎发生在实验上是不可接近的，但胚胎干细胞（ESC）系可以来自早期囊胚的内细胞团。因此，ESCs代表了一种独特而强大的工具，用于研究其他棘手的发育阶段。我们最近已经证明，早期胚胎特有的高频率的有丝分裂错误在体外培养ESC时也是明显的（Zhang et al.，2019 Stem Cell Reports 12：557; Halliwell等人，2020 Stem Cell Reports 14：1009），表明对有丝分裂错误的易感性是早期胚胎细胞的固有特性，ESC将为确定这些错误的机制基础提供一个良好的平台。本项目的总体目标是阐明ESCs有丝分裂错误发生率高的分子机制，并评估染色体获得或丢失（统称为非整倍体）对ESCs发育潜力的影响。