Parental genome unification is highly erroneous in mammalian embryos
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
Categories: cell biology, developmental biology, genetics
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.
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.
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.
Take home message:
- 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.
- 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:
- 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.
- 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.
- 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?
- 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?
Posted on: 14 September 2020 , updated on: 1 October 2020
doi: https://doi.org/10.1242/prelights.24663
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(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.
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