The causes and consequences of mitotic errors in embryonic stem cells

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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.