HIF1A-mediated pathways promote euploid cell survival in chromosomally mosaic embryos
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1.
California Institute of Technology
Abstract
Human fertility is suboptimal in part by error-prone divisions during early cleavage stages, which frequently result in chromosomal aneuploidy. Most human pre-implantation embryos are mosaics of euploid and aneuploid cells, yet those with a low proportion of aneuploid cells can develop to term at rates similar to fully euploid embryos. How embryos manage aneuploidy during early development remains poorly understood – yet this knowledge is crucial for improving fertility outcomes and reducing developmental defects. To investigate these mechanisms, we established a new mouse model of chromosome mosaicism to trace the fate of aneuploid cells during pre-implantation development. We previously used the Mps1 inhibitor reversine to induce aneuploidy. Here, we demonstrate that the more specific Mps1 inhibitor AZ3146 similarly disrupts chromosome segregation but supports higher developmental potential than reversine. AZ3146-treated embryos transiently upregulate hypoxia-inducible factor-1A (HIF1A) without triggering Trp53 activation. Given that pre-implantation embryos develop in a hypoxic environment in vivo, we further explored the role of oxygen tension. Hypoxia exposure in vitro reduced DNA damage in response to Mps1 inhibition and increased the proportion of euploid cells in mosaic epiblast. Conversely, HIF1A inhibition decreased the proportion of aneuploid cells. Together, these findings uncover a role for hypoxia signaling in modulating the response to chromosomal errors and suggest new strategies to improve the developmental potential of mosaic human embryos.
Copyright and License
© 2024, Sanchez-Vasquez et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Acknowledgement
This work was supported by MZG’ National Institutes of Health R01 (R01HD101489) grant. ESV is supported by a Pew Latin America fellowship. We thank the Life Science Editors and the Life Science Editors Foundation for invaluable comments and suggestions on the manuscript, and Ariane Helou for copy editing. Data analysis was performed in the Biological Imaging Facility, with the support of the Caltech Beckman Institute and the Arnold and Mabel Beckman Foundation.
Funding
This work was supported by MZG’ National Institutes of Health R01 (R01HD101489) grant. ESV is supported by a Pew Latin America fellowship.
Contributions
Estefania Sanchez-Vasquez contribution: Conceptualization, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing
Marianne E Bronner contribution: Supervision, Writing – review and editing
Magdalena Zernicka-Goetz contribution: Conceptualization, Funding acquisition, Investigation, Visualization, Methodology, Writing – review and editing
Data Availability
Source data files have been provided for all figures.
The following previously published data sets were used
Deng QRamsköld DReinius BSandberg R (2014) NCBI Gene Expression Omnibus ID GSE45719. Single-cell RNA-Seq reveals dynamic, random monoallelic gene expression in mammalian cells. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE45719
Ethics
We conducted the experiments in this project according to the highest ethical standards. We followed published NIH guidelines, and our protocols and number of animals used were previously approved by the Institutional Animal Care and Use Committee (IACUC) as well as the Institutional Biosafety Committee at the California Institute of Technology (Caltech, protocol number 1772).
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Additional details
Funding
- National Institutes of Health
- R01HD101489
- Pew Charitable Trusts
- Pew Latin America fellowship
Dates
- Submitted
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2024-07-19Preprint posted
- Updated
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2024-11-21Reviewed Preprint version 1
- Updated
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2025-06-20Reviewed Preprint version 2
- Updated
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2025-09-24Reviewed Preprint version 3
- Accepted
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2025-10-14Version of Record published