Menu

Close

The First Mitotic Division of the Human Embryo is Highly Error-prone

Emma Ford, Cerys E. Currie, Deborah M. Taylor, Muriel Erent, Adele L. Marston, Geraldine M. Hartshorne, Andrew D. McAinsh

Preprint posted on July 17, 2020 https://www.biorxiv.org/content/10.1101/2020.07.17.208744v1

Errors make us human – visualizing the first mitotic division in the human embryo reveals a high rate of mitotic errors.

Selected by Grace Lim

Background

The occurrence of aneuploidy in mammalian embryos is widely known to be associated with maternal age, and can lead to miscarriages and genetic disorders (Gruhn et al., 2019). Aneuploidy can occur due to weakened mitotic checkpoints or improper kinetochore-spindle attachments resulting in unequal chromosomal segregation into daughter cells (Siegel and Amon, 2012). These events can take place during meiotic divisions in the egg, but also during the early mitotic divisions of the embryo, independent of maternal age. While early cell division events have been closely studied in mouse embryos (Reichmann et al., 2018), our understanding of aneuploidy in human embryos remains lacking.

Key findings

To gain initial insights into aneuploidy in human embryos, Ford et al. utilized SiR-DNA, a fluorescent DNA probe adapted for live-cell imaging (Lukinavičius et al., 2015), to label chromosomes within the living human embryo. This enabled the authors to visualize the entire process of mitosis with great detail, beginning from the point of nuclear envelope breakdown (NEB) to metaphase, anaphase onset, and end of cytokinesis (Figure 1a, b).

Figure 1: (a) Scheme of key stages of early human embryo development. (b) Time series of a human embryo stained with SiR-DNA labelling the chromosomes, undergoing the first mitotic division. Figure adapted from Ford et al.

Applying this workflow to the first mitotic division (1- to 2-cell stage) of a population of human embryos revealed that the length of the first mitotic division was approximately 3 hours on average, longer than typical somatic cell divisions. Specifically, the extended time taken for prometaphase and metaphase suggests that spindle assembly and establishment of kinetochore-spindle interactions during these stages occur inefficiently. Consistently, as many as 38% of embryos formed abnormal multipolar spindles, and among the other embryos that formed bipolar spindles, a large proportion displayed lagging chromosomes. Despite these mitotic errors, the authors found that these cells entered anaphase at the same time as cells with normal bipolar spindles, pointing to a spindle checkpoint weakening defect whereby anaphase is not delayed until proper spindle assembly and kinetochore-spindle attachments are established.

Finally, the authors visualized the second mitotic division within human embryos, revealing that the second mitotic division is shorter compared to the first mitotic division. In line with the length of mitosis as an indicator of mitotic efficiency, the second mitotic divisions also displayed fewer multipolar divisions and no lagging chromosomes within the group of embryos that were observed. Together, the results suggest that the first mitotic division is a major source of mitotic errors in human embryos.

What I like about this preprint

One of the major challenges of human embryo research is having extremely limited starting material and working within a narrow range of tools that can be applied to answer important questions regarding human embryo development. Moreover, human embryos utilized in research are often ones deemed unsuitable for implantation following IVF, raising questions about the reliability of results drawn from such embryo populations. Here, the authors were able to address these limitations exceptionally by establishing a workflow for efficient live embryo imaging of labelled chromosomes in deselected human embryos, and further corroborating their results with normal human embryos, including those that gave rise to successful pregnancies. Their careful characterization of mitotic divisions occurring within the early human embryo is important for future work in understanding mechanisms of spindle assembly and mitotic checkpoints that regulate proper chromosomal segregations during the earliest stages of life.

Future directions and questions for authors

  1. Apart from SiR-DNA, SiR-tubulin is another established fluorescent probe suitable for visualization of microtubules within living cells. This could be useful in combination with SiR-DNA to understand spindle morphology within the cells of early human embryo. Have the authors tried using SiR-tubulin for this purpose?
  2. The authors performed long-term time-lapse imaging of the embryos for 48 hours, using both brightfield and the far red laser to visualize the mitotic events. However, these imaging conditions could themselves also induce mitotic errors or result in longer duration of mitosis. Have the authors controlled for imaging toxicity effects?

References

Gruhn, J.R., Zielinska, A.P., Shukla, V., Blanshard, R., Capalbo, A., Cimadomo, D., Nikiforov, D., Chan, A.C.-H., Newnham, L.J., Vogel, I., et al. (2019). Chromosome errors in human eggs shape natural fertility over reproductive life span. Science 365, 1466–1469.

Lukinavičius, G., Blaukopf, C., Pershagen, E., Schena, A., Reymond, L., Derivery, E., Gonzalez-Gaitan, M., D’Este, E., Hell, S.W., Wolfram Gerlich, D., et al. (2015). SiR–Hoechst is a far-red DNA stain for live-cell nanoscopy. Nature Communications 6.

Reichmann, J., Nijmeijer, B., Hossain, M.J., Eguren, M., Schneider, I., Politi, A.Z., Roberti, M.J., Hufnagel, L., Hiiragi, T., and Ellenberg, J. (2018). Dual spindle formation in zygotes keeps parental genomes apart in early mammalian embryos.

Siegel, J.J., and Amon, A. (2012). New Insights into the Troubles of Aneuploidy. Annual Review of Cell and Developmental Biology 28, 189–214.

 

Posted on: 28th July 2020

doi: https://doi.org/10.1242/prelights.23497

Read preprint (No Ratings Yet)




  • Have your say

    Your email address will not be published. Required fields are marked *

    This site uses Akismet to reduce spam. Learn how your comment data is processed.

    Sign up to customise the site to your preferences and to receive alerts

    Register here

    preLists in the cell biology category:

    FENS 2020

    A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020

     



    List by Ana Dorrego-Rivas

    Planar Cell Polarity – PCP

    This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.

     



    List by Ana Dorrego-Rivas

    BioMalPar XVI: Biology and Pathology of the Malaria Parasite

    [under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria

     



    List by Gautam Dey, Samantha Seah

    1

    Cell Polarity

    Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.

     



    List by Yamini Ravichandran

    TAGC 2020

    Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20

     



    List by Maiko Kitaoka, Madhuja Samaddar, Miguel V. Almeida, Sejal Davla, Jennifer Ann Black, Gautam Dey

    3D Gastruloids

    A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells)

     



    List by Paul Gerald L. Sanchez and Stefano Vianello

    ECFG15 – Fungal biology

    Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome

     



    List by Hiral Shah

    ASCB EMBO Annual Meeting 2019

    A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

     



    List by Madhuja Samaddar, Ramona Jühlen, Amanda Haage, Laura McCormick, Maiko Kitaoka

    EMBL Seeing is Believing – Imaging the Molecular Processes of Life

    Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019

     



    List by Gautam Dey

    Autophagy

    Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.

     



    List by Sandra Malmgren Hill

    Lung Disease and Regeneration

    This preprint list compiles highlights from the field of lung biology.

     



    List by Rob Hynds

    Cellular metabolism

    A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.

     



    List by Pablo Ranea Robles

    BSCB/BSDB Annual Meeting 2019

    Preprints presented at the BSCB/BSDB Annual Meeting 2019

     



    List by Gautam Dey

    MitoList

    This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.

     



    List by Sandra Franco Iborra

    Biophysical Society Annual Meeting 2019

    Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA

     



    List by Joseph Jose Thottacherry

    ASCB/EMBO Annual Meeting 2018

    This list relates to preprints that were discussed at the recent ASCB conference.

     



    List by Gautam Dey, Amanda Haage

    Also in the developmental biology category:

    Society for Developmental Biology 79th Annual Meeting

    Preprints at SDB 2020

     



    List by Irepan Salvador-Martinez, Martin Estermann

    FENS 2020

    A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020

     



    List by Ana Dorrego-Rivas

    Planar Cell Polarity – PCP

    This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.

     



    List by Ana Dorrego-Rivas

    Cell Polarity

    Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.

     



    List by Yamini Ravichandran

    TAGC 2020

    Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20

     



    List by Maiko Kitaoka, Madhuja Samaddar, Miguel V. Almeida, Sejal Davla, Jennifer Ann Black, Gautam Dey

    3D Gastruloids

    A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells)

     



    List by Paul Gerald L. Sanchez and Stefano Vianello

    ASCB EMBO Annual Meeting 2019

    A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

     



    List by Madhuja Samaddar, Ramona Jühlen, Amanda Haage, Laura McCormick, Maiko Kitaoka

    EDBC Alicante 2019

    Preprints presented at the European Developmental Biology Congress (EDBC) in Alicante, October 23-26 2019.

     



    List by Sergio Menchero, Jesus Victorino, Teresa Rayon, Irepan Salvador-Martinez

    EMBL Seeing is Believing – Imaging the Molecular Processes of Life

    Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019

     



    List by Gautam Dey

    SDB 78th Annual Meeting 2019

    A curation of the preprints presented at the SDB meeting in Boston, July 26-30 2019. The preList will be updated throughout the duration of the meeting.

     



    List by Alex Eve

    Lung Disease and Regeneration

    This preprint list compiles highlights from the field of lung biology.

     



    List by Rob Hynds

    Young Embryologist Network Conference 2019

    Preprints presented at the Young Embryologist Network 2019 conference, 13 May, The Francis Crick Institute, London

     



    List by Alex Eve

    Pattern formation during development

    The aim of this preList is to integrate results about the mechanisms that govern patterning during development, from genes implicated in the processes to theoritical models of pattern formation in nature.

     



    List by Alexa Sadier

    BSCB/BSDB Annual Meeting 2019

    Preprints presented at the BSCB/BSDB Annual Meeting 2019

     



    List by Gautam Dey

    Zebrafish immunology

    A compilation of cutting-edge research that uses the zebrafish as a model system to elucidate novel immunological mechanisms in health and disease.

     



    List by Shikha Nayar
    Close