The causes and consequences of mitotic errors in embryonic stem cells

哺乳动物的发育需要多次快速的细胞分裂，以支持发育中的胚胎的生长和形态发生。由于胚胎内的早期胚胎细胞数量有限，而成年体内的所有细胞都是由早期胚胎细胞形成的，因此这些细胞在细胞分裂过程中发生的错误（有丝分裂错误）可能会造成毁灭性的后果，从先天性缺陷到胚胎致命。然而，尽管在胚胎发生早期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，发育生物学中尚未解决的基本问题是，是什么使胚胎细胞容易受到有丝分裂错误的影响，以及在有丝分裂错误率高的背景下，如何实现稳健的发育。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）系可以从早期囊胚的内细胞群中获得。因此，ESCs是一种独特而强大的工具，用于研究其他难以处理的发展阶段。我们最近证明，在体外培养的ESCs中，早期胚胎的有丝分裂错误特征的高频率也很明显(Zhang等人，2019年干细胞报告12:557；Halliwell et al., 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。该项目的总体目标是阐明ESCs中有丝分裂错误高发生率的分子机制，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。

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.