The causes and consequences of mitotic errors in embryonic stem cells

哺乳动物的发育需要多个快速的细胞分裂，以支持发育中的胚胎的生长和形态发生。由于胚胎中产生所有成年细胞的早期胚胎细胞数量有限，这些细胞在细胞分裂过程中发生的错误(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死亡。然而，尽管在早期胚胎发育过程中保持基因组完整性至关重要，胚胎细胞尤其容易出现有丝分裂错误。因此，发育生物学中尚未回答的基本问题是，是什么使胚胎细胞容易受到有丝分裂错误的影响，以及如何在高有丝分裂错误的背景下实现强劲的发育。尽管从实验上无法获得早期人类胚胎发生，但胚胎干细胞(ESC)系可以从早期囊胚的内部细胞团中衍生出来。因此，胚胎干细胞是研究原本难以处理的发育阶段的一个独特而强大的工具。我们最近已经证明了早期胚胎特有的高频率的有丝分裂错误在ESCs的体外培养中也是明显的(Zhang等人，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属性，ESC将为确定这些错误的A2021-Entry-WR-DTP-Case-Form-A-baric提供一个很好的平台。本项目的总体目标是阐明胚胎干细胞中高发生率有丝分裂错误的分子机制，并评估染色体获得或丢失(统称为非整倍体)对胚胎干细胞发育潜力的影响。

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.