Chromosome segregation regulation in human zygotes: altered mitotic histone phosphorylation dynamics underlying centromeric targeting of the chromosomal passenger complex

Werken, Christine van de; Santos, Margarida Avo; Laven, Joop S.E.; Eleveld, Cindy; Fauser, Bart C.J.M.; Lens, Susanne M.A.; Baart, Esther B.

doi:10.1093/humrep/dev186

Cited by 10 publications

(7 citation statements)

References 81 publications

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“…38 Our results showed higher levels of In mitotic cells, Aurora B promotes proper chromosome segregation in part by regulating chromosome alignment at the metaphase plate; this may function to ensure embryonic euploidy. 39,40 Disruption of Aurora B function leads to chromosome segregation defects, including nondisjunction, lagging chromosomes and cytokinesis failure. 41 The frequent observation of micronuclei in embryos suggests defects in chromosome stability.…”

Section: Discussionmentioning

confidence: 99%

Aurora B prevents aneuploidy via MAD2 during the first mitotic cleavage in oxidatively damaged embryos

et al. 2019

Cell Proliferation

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Objectives: A high rate of chromosome aneuploidy is exhibited in in vitro fertilization (IVF)-derived embryos. Our previous experiments suggested that reactive oxygen species (ROS) can activate Mad2, a key protein in the spindle assembly checkpoint (SAC), and delay the first mitotic, providing time to prevent the formation of embryonic aneuploidy. We aimed to determine whether mitotic kinase Aurora B was involved in the SAC function to prevent aneuploidy in IVF-derived embryos. Materials and Methods:We analysed aneuploidy formation and repair during embryo pre-implantation via 4ʹ,6-diamidino-2-phenylindole (DAPI) staining and karyotype analysis. We assessed Aurora B activation by immunofluorescence and investigated the effect of Aurora B inhibition on embryo injury-related variables, such as embryonic development, ROS levels, mitochondrial membrane potential and γH2AX-positive expression. Results:We observed the expression and phosphorylation of Thr232 in Aurora B in oxidative stress-induced zygotes. Moreover, inhibition of Aurora B caused chromosome mis-segregation, abnormal spindle structures, abnormal chromosome number and reduced expression of Mad2 in IVF embryos. Our results suggest that Aurora B causes mitotic arrest and participates in SAC via Mad2 and H3S10P, which is required for self-correction of aneuploidies. Conclusions:We demonstrate here that oxidative stress-induced DNA damage triggers Aurora B-mediated activation of SAC, which prevents aneuploidy at the first mitotic cleavage in early mouse IVF embryos.

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Section: Discussionmentioning

confidence: 99%

Aurora B prevents aneuploidy via MAD2 during the first mitotic cleavage in oxidatively damaged embryos

et al. 2019

Cell Proliferation

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“…Mutational inactivation of SAC components is known to cause CIN and aneuploidy in certain cancers, with affected cells exiting mitosis despite microtubule disruption [31]. This checkpoint appears similarly weakened [25], though still present [32], during cleavage-stage development in humans. Supporting this hypothesis, several key components of the SAC, including BUB1 and MAD2 , show significantly greater expression in hatched blastocysts than at earlier cleavage stages [33].…”

Section: Molecular Factors Contributing To Mitotic Errormentioning

confidence: 99%

Mosaicism in Preimplantation Human Embryos: When Chromosomal Abnormalities Are the Norm

2017

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Along with errors in meiosis, mitotic errors during post-zygotic cell division contribute to pervasive aneuploidy in human embryos. Relatively little is known, however, about the genesis of these errors or their fitness consequences. Rapid technological advances are helping close this gap, revealing diverse molecular mechanisms contributing to mitotic error. These include altered cell cycle checkpoints, aberrations of the centrosome, and failed chromatid cohesion, mirroring findings from cancer biology. Recent studies are challenging the idea that mitotic error is abnormal, emphasizing that the fitness impacts of mosaicism depend on its scope and severity. In light of these findings, technical and philosophical limitations of various screening approaches are discussed, along with avenues for future research.

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“…Finally, paternal and maternal genome of mammalian zygotes have a different chromatin configuration (Burton and Torres-Padilla, 2014). Epigenetic asymmetry in the human zygote makes paternal chromosomes more susceptible to kinetochore attachment and mis-segregation errors (van de Werken et al, 2015). Interestingly, a recent study in mice uncovered that DNA damage repair pathways are also actively involved in zygotic reprogramming of the paternal genome (Ladstatter and Tachibana-Konwalski, 2016).…”

Section: The Dna Damage Response and Repair Pathwaymentioning

confidence: 99%

A speculative outlook on embryonic aneuploidy: Can molecular pathways be involved?

Tšuiko

Jatsenko

Lalitkumar

et al. 2019

Developmental Biology

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The journey of embryonic development starts at oocyte fertilization, which triggers a complex cascade of events and cellular pathways that guide early embryogenesis. Recent technological advances have greatly expanded our knowledge of cleavage-stage embryo development, which is characterized by an increased rate of whole-chromosome losses and gains, mixoploidy, and atypical cleavage morphokinetics. Embryonic aneuploidy significantly contributes to implantation failure, spontaneous miscarriage, stillbirth or congenital birth defects in both natural and assisted human reproduction. Essentially, early embryo development is strongly determined by maternal factors. Owing to considerable limitations associated with human oocyte and embryo research, the use of animal models is inevitable. However, cellular and molecular mechanisms driving the error-prone early stages of development are still poorly described. In this review, we describe known events that lead to aneuploidy in mammalian oocytes and preimplantation embryos. As the processes of oocyte and embryo development are rigorously regulated by multiple signal-transduction pathways, we explore the putative role of signaling pathways in genomic integrity maintenance. Based on the existing evidence from human and animal data, we investigate whether critical early developmental pathways, like Wnt, Hippo and MAPK, together with distinct DNA damage response and DNA repair pathways can be associated with embryo genomic instability, a question that has, so far, remained largely unexplored.

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Chromosome segregation regulation in human zygotes: altered mitotic histone phosphorylation dynamics underlying centromeric targeting of the chromosomal passenger complex

Abstract: This study was funded by the Portuguese Fundação para a Ciência e Tecnologia and the Netherlands Organization for Scientific Research. The authors have no conflicts of interest to declare.

Cited by 10 publications

References 81 publications

Aurora B prevents aneuploidy via MAD2 during the first mitotic cleavage in oxidatively damaged embryos

Aurora B prevents aneuploidy via MAD2 during the first mitotic cleavage in oxidatively damaged embryos

Mosaicism in Preimplantation Human Embryos: When Chromosomal Abnormalities Are the Norm

A speculative outlook on embryonic aneuploidy: Can molecular pathways be involved?

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