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

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          Abstract

          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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          Most cited references50

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          Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores

          The Aurora/Ipl1 family of protein kinases plays multiple roles in mitosis and cytokinesis. Here, we describe ZM447439, a novel selective Aurora kinase inhibitor. Cells treated with ZM447439 progress through interphase, enter mitosis normally, and assemble bipolar spindles. However, chromosome alignment, segregation, and cytokinesis all fail. Despite the presence of maloriented chromosomes, ZM447439-treated cells exit mitosis with normal kinetics, indicating that the spindle checkpoint is compromised. Indeed, ZM447439 prevents mitotic arrest after exposure to paclitaxel. RNA interference experiments suggest that these phenotypes are due to inhibition of Aurora B, not Aurora A or some other kinase. In the absence of Aurora B function, kinetochore localization of the spindle checkpoint components BubR1, Mad2, and Cenp-E is diminished. Furthermore, inhibition of Aurora B kinase activity prevents the rebinding of BubR1 to metaphase kinetochores after a reduction in centromeric tension. Aurora B kinase activity is also required for phosphorylation of BubR1 on entry into mitosis. Finally, we show that BubR1 is not only required for spindle checkpoint function, but is also required for chromosome alignment. Together, these results suggest that by targeting checkpoint proteins to kinetochores, Aurora B couples chromosome alignment with anaphase onset.
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            Chromosomal passengers: conducting cell division.

            Mitosis and meiosis are remarkable processes during which cells undergo profound changes in their structure and physiology. These events are orchestrated with a precision that is worthy of a classical symphony, with different activities being switched on and off at precise times and locations throughout the cell. One essential 'conductor' of this symphony is the chromosomal passenger complex (CPC), which comprises Aurora-B protein kinase, the inner centromere protein INCENP, survivin and borealin (also known as Dasra-B). Studies of the CPC are providing insights into its functions, which range from chromosome-microtubule interactions to sister chromatid cohesion to cytokinesis, and constitute one of the most dynamic areas of ongoing mitosis and meiosis research.
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              Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential

              Most human pre-implantation embryos are mosaics of euploid and aneuploid cells. To determine the fate of aneuploid cells and the developmental potential of mosaic embryos, here we generate a mouse model of chromosome mosaicism. By treating embryos with a spindle assembly checkpoint inhibitor during the four- to eight-cell division, we efficiently generate aneuploid cells, resulting in embryo death during peri-implantation development. Live-embryo imaging and single-cell tracking in chimeric embryos, containing aneuploid and euploid cells, reveal that the fate of aneuploid cells depends on lineage: aneuploid cells in the fetal lineage are eliminated by apoptosis, whereas those in the placental lineage show severe proliferative defects. Overall, the proportion of aneuploid cells is progressively depleted from the blastocyst stage onwards. Finally, we show that mosaic embryos have full developmental potential, provided they contain sufficient euploid cells, a finding of significance for the assessment of embryo vitality in the clinic.
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                Author and article information

                Contributors
                stlizhiling@126.com
                Journal
                Cell Prolif
                Cell Prolif
                10.1111/(ISSN)1365-2184
                CPR
                Cell Proliferation
                John Wiley and Sons Inc. (Hoboken )
                0960-7722
                1365-2184
                01 July 2019
                September 2019
                : 52
                : 5 ( doiID: 10.1111/cpr.v52.5 )
                : e12657
                Affiliations
                [ 1 ] Reproductive Center, The First Affiliated Hospital of Shantou University Medical College Shantou University Shantou China
                [ 2 ] Laboratory for Reproductive Immunology, Hospital & Institute of Obstetrics & Gynecology Fudan University Shanghai Medical College Shanghai China
                Author notes
                [*] [* ] Correspondence

                Zhiling Li, Reproductive Center, The First Affiliated Hospital of Shantou University Medical College, Shantou University, No. 57, Changping Road, Shantou 515000, Guangdong, China.

                Email: stlizhiling@ 123456126.com

                Author information
                https://orcid.org/0000-0001-7661-6686
                https://orcid.org/0000-0003-4884-1194
                https://orcid.org/0000-0002-1467-0641
                Article
                CPR12657
                10.1111/cpr.12657
                6797512
                31264311
                c8045cab-4cac-4bf8-bbc4-e073b74211cc
                © 2019 The Authors. Cell Proliferation published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 23 March 2019
                : 07 May 2019
                : 27 May 2019
                Page count
                Figures: 6, Tables: 3, Pages: 14, Words: 7530
                Funding
                Funded by: Guangdong Provincial Science and Technology Project
                Award ID: 2016A020218015
                Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;
                Award ID: 81871223
                Award ID: 81671536
                Award ID: 81471522
                Award ID: 2014A030313482
                Funded by: Natural Science Foundation of Guangdong Province , open-funder-registry 10.13039/501100003453;
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                September 2019
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.2 mode:remove_FC converted:05.12.2019

                Cell biology
                aurora b,chromosome aneuploid,in vitro fertilization,oxidative stress,spindle
                Cell biology
                aurora b, chromosome aneuploid, in vitro fertilization, oxidative stress, spindle

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