@article{223e33fb6a7f4a799856597c254d06d8,
title = "Parental genome unification is highly error-prone in mammalian embryos",
abstract = "Most human embryos are aneuploid. Aneuploidy frequently arises during the early mitotic divisions of the embryo, but its origin remains elusive. Human zygotes that cluster their nucleoli at the pronuclear interface are thought to be more likely to develop into healthy euploid embryos. Here, we show that the parental genomes cluster with nucleoli in each pronucleus within human and bovine zygotes, and clustering is required for the reliable unification of the parental genomes after fertilization. During migration of intact pronuclei, the parental genomes polarize toward each other in a process driven by centrosomes, dynein, microtubules, and nuclear pore complexes. The maternal and paternal chromosomes eventually cluster at the pronuclear interface, in direct proximity to each other, yet separated. Parental genome clustering ensures the rapid unification of the parental genomes on nuclear envelope breakdown. However, clustering often fails, leading to chromosome segregation errors and micronuclei, incompatible with healthy embryo development.",
keywords = "aneuploidy, centrosomes, chromosome segregation, dynein, fertilization, genome organization, human embryo, microtubules, nuclear pore complex, spindle",
author = "Tommaso Cavazza and Yuko Takeda and Politi, {Antonio Z.} and Magomet Aushev and Patrick Aldag and Clara Baker and Meenakshi Choudhary and Jonas Bucevi{\v c}ius and Gra{\v z}vydas Lukinavi{\v c}ius and Kay Elder and Martyn Blayney and Andrea Lucas-Hahn and Heiner Niemann and Mary Herbert and Melina Schuh",
note = "Funding Information: We thank L. Pieper and M.W. Kriesten (Westfleisch SCE mbH, Hamm, Germany) for enabling this research by donating bovine ovaries; the MPI-BPC drivers for collecting ovaries; M. Daniel (MPI-BPC) for assistance in coordinating ovary collection; J. Uraji and K. Menelaou (MPI-BPC) for help in providing the human embryo videos; N. Sharma, C. So, A. Webster (MPI-BPC), and A. Zielinska (Imperial College, London, UK) for technical advice; S. Munro (LMB, Cambridge, UK), A. Musacchio (MPI-Molecular Physiology, Dortmund, Germany), and J. Ellenberg (EMBL, Heidelberg, Germany) for plasmids; V. Cordes (MPI-BPC) for antibodies; Z. Holubcov{\'a} (Department of Histology and Embryology, Masaryk University, Czech Republic) for discussions about human zygotes; M.E. Torres-Padilla (IES, Munich, Germany) for discussion about Nup98; the Bioimaging Unit (Newcastle University, UK), the Live-cell imaging facility (MPI-BPC), and P. L{\'e}n{\'a}rt (MPI-BPC) for discussion and support; C. Thomas (MPI-BPC), L. Wartosch (MPI-BPC), and Life Science Editors for critical comments on the manuscript; members of the Schuh lab for discussions. The work on human zygotes was funded by the Wellcome Human Developmental Biology Initiative (HDBI; 215116/Z/18/Z) and a Wellcome Centre grant (203105/Z/16/Z). The research leading to these results received financial support from the Max Planck Society and Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy (EXC 2067/1-390729940) and a DFG Leibniz Prize (SCHU 3047/1-1) to M.S. T.C and M.S. conceived the study. T.C. and M.S. designed experiments. T.C. performed all bovine experiments. M.H. and Y.T. designed the human zygote experiments. Y.T. performed all human experiments, except for the recording of the human zygote in Figure 1F and in part III of Video S1, done by M.A. T.C. A.Z.P. and M.S. designed methods for data analysis. A.Z.P. wrote all in-house-developed scripts and plugins. T.C. and A.Z.P. analyzed the data. P.A. A.L.-H. and H.N. supervised the establishment of the bovine experimental system. Y.T. and M.H. established the human live imaging system. M.H. and M.C. supervised the work at the Newcastle Fertility Centre at Life. M.B. and K.E. supervised the work at Bourn Hall clinic. C.B. recorded the human embryo GERI videos. J.B. and G.L. produced the 5-580CP-Hoechst. T.C. and M.S. wrote the manuscript and prepared the figures with input from all authors. M.S. supervised the study. The authors declare no competing interests. Funding Information: We thank L. Pieper and M.W. Kriesten (Westfleisch SCE mbH, Hamm, Germany) for enabling this research by donating bovine ovaries; the MPI-BPC drivers for collecting ovaries; M. Daniel (MPI-BPC) for assistance in coordinating ovary collection; J. Uraji and K. Menelaou (MPI-BPC) for help in providing the human embryo videos; N. Sharma, C. So, A. Webster (MPI-BPC), and A. Zielinska (Imperial College, London, UK) for technical advice; S. Munro (LMB, Cambridge, UK), A. Musacchio (MPI-Molecular Physiology, Dortmund, Germany), and J. Ellenberg (EMBL, Heidelberg, Germany) for plasmids; V. Cordes (MPI-BPC) for antibodies; Z. Holubcov{\'a} (Department of Histology and Embryology, Masaryk University, Czech Republic) for discussions about human zygotes; M.E. Torres-Padilla (IES, Munich, Germany) for discussion about Nup98; the Bioimaging Unit (Newcastle University, UK), the Live-cell imaging facility (MPI-BPC), and P. L{\'e}n{\'a}rt (MPI-BPC) for discussion and support; C. Thomas (MPI-BPC), L. Wartosch (MPI-BPC), and Life Science Editors for critical comments on the manuscript; members of the Schuh lab for discussions. The work on human zygotes was funded by the Wellcome Human Developmental Biology Initiative (HDBI; 215116/Z/18/Z ) and a Wellcome Centre grant ( 203105/Z/16/Z ). The research leading to these results received financial support from the Max Planck Society and Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany{\textquoteright}s Excellence Strategy ( EXC 2067/1-390729940 ) and a DFG Leibniz Prize ( SCHU 3047/1-1 ) to M.S. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = may,
day = "27",
doi = "10.1016/j.cell.2021.04.013",
language = "English",
volume = "184",
pages = "2860--2877.e22",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "11",
}
