Close

Parental genome unification is highly erroneous in mammalian embryos

Tommaso Cavazza, Antonio Z Politi, Patrick Aldag, Clara Baker, Kay Elder, Martyn Blayney, Andrea Lucas-Hahn, Heiner Niemann, Melina Schuh

Preprint posted on 27 August 2020 https://www.biorxiv.org/content/10.1101/2020.08.27.269779v1

Article now published in Cell at http://dx.doi.org/10.1016/j.cell.2021.04.013

Parental genomes work in concert to prevent fatal errors at the start of life.

Selected by Madhuja Samaddar

Background:

Aneuploidy, arising from chromosome segregation errors during gamete production (meiosis) or early embryonic divisions (mitosis), is common in both natural and assisted fertilization, and 50-70% human embryos are estimated to be aneuploid. This is a leading cause of infertility and affects multiple stages of successful reproduction, from improper blastocyst development, implantation failure, spontaneous miscarriage, to stillbirth and congenital defects. However, the mechanisms driving early embryonic aneuploidy are poorly understood owing to the ethical restrictions of working with live human embryos and the technical challenges with observing chromosome segregation in live animal embryos without altering their biology. What are the mechanisms guiding parental genome unification and chromosome segregation in early post-fertilization embryos (which differ from somatic cells on account of having two pronuclei)? And why do these mechanisms fail so very often? A new study by Cavazza et al. (bioRxiv, August 2020) provides new insights into these questions.

 

Key Findings:

The authors demonstrate that the maternal and paternal genomes initiate unification much earlier than was previously expected. The migration of pronuclei coincides with chromosome condensation and clustering at the intact pronuclear surface, even before nuclear envelope breakdown. This is described as pre-unification and both chromosome condensation and clustering are key steps in the process; failure in either step for a single pronucleus significantly elevates the chances of mitotic aneuploidy. By bringing the parental genomes in close proximity and exposing the kinetochores, pre-unification enhances the efficiency of chromosome capture by microtubules, thus preventing mitotic errors such as chromosome congression defects, lagging chromosomes and formation of micronuclei.

Defects in condensation or clustering during parental genome pre-unification: consequences on chromosome segregation (Adapted from Figure 7 of the preprint under a CC-BY-NC-ND 4.0 International license.)

 

Next, the authors demonstrate the mechanism by which pre-unification is achieved. They find that centrosomes play a central role by determining the site of chromosome clustering at the interface of the pronuclei. Further, this clustering involves microtubules and is mediated by dynein. But what is the signal marking the pronuclear interface? Nuclear-pore complexes are found to be selectively enriched at this interface, and chromosome clustering is driven by dynein-dependent pulling on the nuclear-pore complexes. Other nuclear membrane proteins do not show this characteristic polarization and remain dispersed along the entire nuclear envelope.

Enrichment of nuclear-pore complexes at the pronuclear interface allow the condensed chromosomes to cluster in close proximity to centrosomes. (Adapted from Figure 5 of the preprint under a CC-BY-NC-ND 4.0 International license.)

 

Finally, nucleoli are shown to colocalize with chromatin in bovine embryos thus establishing nucleolar clustering as a convenient proxy for chromosome clustering. Nucleoli are distinct structures that are easily identifiable in transmitted light images, and the authors examined existing videos of live human embryos from routine IVF treatment procedures. Interestingly, similar to chromatin compaction and clustering, these videos reveal nucleolar migration towards the pronuclear interface, and that embryos with clustered nucleoli were more likely to subsequently develop into normal blastocysts.

Nucleolar clustering in human embryos as a predictor for developmental success. (Adapted from Figure 6 of the preprint under a CC-BY-NC-ND 4.0 International license.)

 

Take home message:

  1. Parental genome pre-unification is required for error-free chromosome segregation; the presence of a pronucleus with an uncondensed or unclustered genome typically leads to embryonic aneuploidy.
  2. Pronuclear migration and chromatin clustering occur simultaneously and are driven by a shared cellular machinery, with the common goal of uniting the parental genomes at the pronuclear surface and improving efficiency of chromosome capture.

 

Why I chose this preprint:

Using a high-resolution imaging system, the authors for the first-time capture chromosome segregation in live embryos, shedding light on early post-fertilization events that determine subsequent developmental success. The images and videos of the first mitotic division in bovine embryos offer a fascinating glimpse into the beginning of life, and the dangers associated with being dependent on an error-prone system to unite parental genomes and ensure genetic diversity. Together with the new insights from existing information on human embryos, they demonstrate that subsequent developmental success can be predicted by examining parental genome pre-unification, very early in embryogenesis.

This study is also a case in point that one size doesn’t fit all. Mice aren’t necessarily the best models for studying all aspects of mammalian biology, even though they are the most commonly used. In the case of early embryonic development, mice engage a strategy of multiple acentriolar microtubule organizing centers, potentially enhancing the efficiency of chromosome capture by microtubules and resulting in significantly lowered aneuploidy rates. By using bovine embryos instead, the authors are able to successfully investigate a mechanism that more closely recapitulates the human scenario.

 

Questions for the authors:

  1. Aneuploidy originating during meiosis is known to increase with age and affect the quality of gametes. Do you think that higher parental age also leads to an increased rate of mitotic aneuploidy early in embryonic development, making it a double whammy? Do the mechanisms underlying early condensation and clustering of chromosomes in migrating pronuclei become inefficient with age? Maybe the anonymized information associated with the videos of the human embryos could shed some light on this, via the nucleolar clustering proxy.
  2. You mentioned that “human zygotes with clustered nucleoli were significantly more likely to develop into blastocysts than zygotes with scattered nucleoli”. Is nucleolar positioning routinely used by IVF clinics as one of the parameters that signals favorable preimplantation development? If not, this could probably be adopted in routine screenings as well.
  3. In the images in Figure 2A, the ‘uncondensed’ pronucleus is understandably larger but the ‘unclustered’ is also larger is size. Is this a common feature of pronuclei demonstrating either the uncondensed or unclustered phenotypes, and is this a predictor of mitotic errors following nuclear envelope breakdown?
  4. What do you think could be the mechanism for selective localization of nuclear-pore complexes at the pronuclear interface? What are the cues that enable this polarization while other nuclear membrane proteins remain uniformly dispersed?

Tags: aneuploidy, chromosome segregation, embryonic development, fertilization, mitosis

Posted on: 14 September 2020 , updated on: 1 October 2020

doi: https://doi.org/10.1242/prelights.24663

Read preprint (No Ratings Yet)

Response from the authors

Melina Schuh and Tommaso Cavazza shared

  • Aneuploidy originating during meiosis is known to increase with age and affect the quality of gametes. Do you think that higher parental age also leads to an increased rate of mitotic aneuploidy early in embryonic development, making it a double whammy? Do the mechanisms underlying early condensation and clustering of chromosomes in migrating pronuclei become inefficient with age? Maybe the anonymized information associated with the videos of the human embryos could shed some light on this, via the nucleolar clustering proxy.

This is an excellent suggestion to correlate the efficiency of nucleolar clustering with the parents’ age. Overall, there does not appear to be a major age-effect on mitotic aneuploidy though (see for instance the studies that we cite in the paper). However, more extensive studies might of course reveal more subtle differences in the future.

Tesarik and Greco, 1999; Scott et al, 2003; Lee and Kiessling, 2017; McCoy et al., 2015; McCoy, 2017; van Echten-Arends et al., 2011; Vanneste et al., 2009; Vera-Rodriguez et al., 2015

 

  • You mentioned that “human zygotes with clustered nucleoli were significantly more likely to develop into blastocysts than zygotes with scattered nucleoli”. Is nucleolar positioning routinely used by IVF clinics as one of the parameters that signals favorable preimplantation development? If not, this could probably be adopted in routine screenings as well.

There are quite a few studies (examples below) that correlated the developmental capacity of human zygotes with the position of their nucleoli (nucleolar precursor bodies in this stage). Different studies came to slightly different conclusions though. This might be partially due to the fact that early studies assessed zygotes at single time points. This might have influenced the results in some of these studies because clustering is a dynamic, gradual process, and should ideally be assessed just before NEBD. However, most studies seem to agree that nucleolar clustering is an indicator of high zygote quality, as confirmed by our analysis of live human embryos.

We hence agree that nucleolar clustering could be used to predict the developmental capacity of embryos. It is currently not commonly used for the following reasons:

  • If and how the patterns of nucleolar positions in zygotes correlate with healthy embryo development was somewhat controversial (see more detailed explanation above).
  • The biological meaning of the clustering of nucleoli was unknown.
  • IVF clinics in most countries are allowed to culture embryos up to the blastocyst stage. In this way, the clinics can assess the entire process of embryo development. Monitoring the position of the nucleoli before NEBD could still provide a useful additional parameter for determining the quality of the embryo and should hence be considered. Assessing nucleolar clustering should be even more useful in countries like Germany though, where IVF clinics have to select the embryos for transfer in the zygote stage already. Monitoring the clustering of the nucleoli should be particularly helpful under these circumstances.

Fulka et al., 2015; Guerif et al., 2007; James et al., 2006; Swain, 2013; Azzarello et al., 2012; Coticchio et al., 2018; Faramarzi et al., 2018

 

  • In the images in Figure 2A, the ‘uncondensed’ pronucleus is understandably larger but the ‘unclustered’ is also larger is size. Is this a common feature of pronuclei demonstrating either the uncondensed or unclustered phenotypes, and is this a predictor of mitotic errors following nuclear envelope breakdown?

This is an interesting point that we investigated by quantifying the pronuclear radius for the three categories. This revealed that there was no significant difference for the three groups. It is possible that the pronuclei in this example appear different in size due to their orientation before generating a maximum intensity projection.

 

  • What do you think could be the mechanism for selective localization of nuclear-pore complexes at the pronuclear interface? What are the cues that enable this polarization while other nuclear membrane proteins remain uniformly dispersed?

Our data suggest that the centrosomes determine where the nuclear pore complexes cluster, via dynein and microtubules. The position of the other nuclear membrane proteins appears to be independent of the position of the nuclear pore complexes. Our data suggest that the chromosomes are directly attached to the nuclear pore complexes via their arms. The precise nature of this interaction is still unclear though.

Have your say

Your email address will not be published.

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:

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:

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

Also in the genetics category:

Semmelweis Symposium 2022: 40th anniversary of international medical education at Semmelweis University

This preList contains preprints discussed during the 'Semmelweis Symposium 2022' (7-9 November), organised around the 40th anniversary of international medical education at Semmelweis University covering a wide range of topics.

 



List by Nándor Lipták

20th “Genetics Workshops in Hungary”, Szeged (25th, September)

In this annual conference, Hungarian geneticists, biochemists and biotechnologists presented their works. Link: http://group.szbk.u-szeged.hu/minikonf/archive/prg2021.pdf

 



List by Nándor Lipták

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

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

TAGC 2020

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

 



List by Maiko Kitaoka et al.

ECFG15 – Fungal biology

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

 



List by Hiral Shah

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
Close