The First Mitotic Division of the Human Embryo is Highly Error-prone
Posted on: 28 July 2020
Preprint posted on 17 July 2020
Errors make us human – visualizing the first mitotic division in the human embryo reveals a high rate of mitotic errors.
Selected by Grace Lim
Categories: cell biology, developmental biology
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
- 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?
- 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.
doi: https://doi.org/10.1242/prelights.23497
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