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

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

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.

 

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

Also in the cell biology category:

Long range mutual activation establishes Rho and Rac polarity during cell migration

Henry De Belly, Andreu Fernandez Gallen, Evelyn Strickland, et al.

Selected by 22 October 2024

Vibha SINGH

Cell Biology

Intracellular diffusion in the cytoplasm increases with cell size in fission yeast

Catherine Tan, Michael C. Lanz, Matthew Swaffer, et al.

Selected by 18 October 2024

Leeba Ann Chacko, Sameer Thukral

Cell Biology

Deciphering the nanoscale architecture of presynaptic actin using a micropatterned presynapse-on-glass model

Sofia Tumminia, Louisa Mezache, Theresa Wiesner, et al.

Selected by 18 October 2024

Felipe Del Valle Batalla

Neuroscience

Also in the developmental biology category:

Actin-based deformations of the nucleus control multiciliated ependymal cell differentiation

Marianne Basso, Alexia Mahuzier, Syed Kaabir Ali, et al.

Selected by 30 October 2024

Ryan Harrison

Developmental Biology

HIF1A contributes to the survival of aneuploid and mosaic pre-implantation embryos

Estefania Sanchez-Vasquez, Marianne E. Bronner, Magdalena Zernicka-Goetz

Selected by 11 October 2024

Anchel De Jaime Soguero

Developmental Biology

Axis reset is rate limiting for onset of whole-body regenerative abilities during planarian development

Clare L.T. Booth, Brian C. Stevens, Clover A. Stubbert, et al.

Selected by 10 October 2024

Isabella Cisneros

Developmental Biology

preLists in the cell biology category:

BSCB-Biochemical Society 2024 Cell Migration meeting

This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.

 



List by Reinier Prosee

‘In preprints’ from Development 2022-2023

A list of the preprints featured in Development's 'In preprints' articles between 2022-2023

 



List by Alex Eve, Katherine Brown

preLights peer support – preprints of interest

This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.

 



List by preLights peer support

The Society for Developmental Biology 82nd Annual Meeting

This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.

 



List by Joyce Yu, Katherine Brown

CSHL 87th Symposium: Stem Cells

Preprints mentioned by speakers at the #CSHLsymp23

 



List by Alex Eve

Journal of Cell Science meeting ‘Imaging Cell Dynamics’

This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.

 



List by Helen Zenner

9th International Symposium on the Biology of Vertebrate Sex Determination

This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.

 



List by Martin Estermann

Alumni picks – preLights 5th Birthday

This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.

 



List by Sergio Menchero et al.

CellBio 2022 – An ASCB/EMBO Meeting

This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.

 



List by Nadja Hümpfer et al.

Fibroblasts

The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!

 



List by Osvaldo Contreras

EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)

A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.

 



List by Alex Eve

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 Dey Lab, 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 et al.

3D Gastruloids

A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.

 



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 et al.

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 Dey Lab

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 Dey Lab

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 Dey Lab, Amanda Haage

Also in the developmental biology category:

BSDB/GenSoc Spring Meeting 2024

A list of preprints highlighted at the British Society for Developmental Biology and Genetics Society joint Spring meeting 2024 at Warwick, UK.

 



List by Joyce Yu, Katherine Brown

GfE/ DSDB meeting 2024

This preList highlights the preprints discussed at the 2024 joint German and Dutch developmental biology societies meeting that took place in March 2024 in Osnabrück, Germany.

 



List by Joyce Yu

‘In preprints’ from Development 2022-2023

A list of the preprints featured in Development's 'In preprints' articles between 2022-2023

 



List by Alex Eve, Katherine Brown

preLights peer support – preprints of interest

This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.

 



List by preLights peer support

The Society for Developmental Biology 82nd Annual Meeting

This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.

 



List by Joyce Yu, Katherine Brown

CSHL 87th Symposium: Stem Cells

Preprints mentioned by speakers at the #CSHLsymp23

 



List by Alex Eve

Journal of Cell Science meeting ‘Imaging Cell Dynamics’

This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.

 



List by Helen Zenner

9th International Symposium on the Biology of Vertebrate Sex Determination

This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.

 



List by Martin Estermann

Alumni picks – preLights 5th Birthday

This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.

 



List by Sergio Menchero et al.

CellBio 2022 – An ASCB/EMBO Meeting

This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.

 



List by Nadja Hümpfer et al.

2nd Conference of the Visegrád Group Society for Developmental Biology

Preprints from the 2nd Conference of the Visegrád Group Society for Developmental Biology (2-5 September, 2021, Szeged, Hungary)

 



List by Nándor Lipták

Fibroblasts

The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!

 



List by Osvaldo Contreras

EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)

A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.

 



List by Alex Eve

EMBL Conference: From functional genomics to systems biology

Preprints presented at the virtual EMBL conference "from functional genomics and systems biology", 16-19 November 2020

 



List by Jesus Victorino

Single Cell Biology 2020

A list of preprints mentioned at the Wellcome Genome Campus Single Cell Biology 2020 meeting.

 



List by Alex Eve

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 et al.

3D Gastruloids

A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.

 



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 et al.

EDBC Alicante 2019

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

 



List by Sergio Menchero et al.

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 Dey Lab

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 Dey Lab

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