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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 August 27, 2020 https://www.biorxiv.org/content/10.1101/2020.08.27.269779v1

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: 14th September 2020

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

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