Developmental signals control chromosome segregation fidelity during pluripotency and neurogenesis by modulating replicative stress

Anchel de Jaime-Soguero, Janina Hattemer, Anja Bufe, Alexander Haas, Jeroen Berg, Vincent Batenburg, Biswajit Das, Barbara Marco, Stefania Androulaki, Nicolas Böhly, Jonathan J. M. Landry, Brigitte Schoell, Viviane S. Rosa, Laura Villacorta, Yagmur Baskan, Marleen Trapp, Vladimir Benes, Andrei Chabes, Marta Shahbazi, Anna Jauch, Ulrike Engel, Annarita Patrizi, Rocio Sotillo, Alexander Oudenaarden, Josephine Bageritz, Julieta Alfonso, Holger Bastians and Sergio P. Acebrón ()
Additional contact information
Anchel de Jaime-Soguero: Heidelberg University
Janina Hattemer: Heidelberg University
Anja Bufe: Heidelberg University
Alexander Haas: University Medical Center Göttingen (UMG)
Jeroen Berg: Oncode Institute
Vincent Batenburg: Oncode Institute
Biswajit Das: Umeå University
Barbara Marco: University Hospital Heidelberg and German Cancer Research Center (DKFZ)
Stefania Androulaki: Heidelberg University
Nicolas Böhly: University Medical Center Göttingen (UMG)
Jonathan J. M. Landry: European Molecular Biology Laboratory (EMBL)
Brigitte Schoell: Heidelberg University
Viviane S. Rosa: MRC Laboratory of Molecular Biology
Laura Villacorta: European Molecular Biology Laboratory (EMBL)
Yagmur Baskan: Heidelberg University
Marleen Trapp: German Cancer Research Center (DKFZ)
Vladimir Benes: European Molecular Biology Laboratory (EMBL)
Andrei Chabes: Umeå University
Marta Shahbazi: MRC Laboratory of Molecular Biology
Anna Jauch: Heidelberg University
Ulrike Engel: Bioquant
Annarita Patrizi: German Cancer Research Center (DKFZ)
Rocio Sotillo: German Cancer Research Center (DKFZ)
Alexander Oudenaarden: Oncode Institute
Josephine Bageritz: Heidelberg University
Julieta Alfonso: University Hospital Heidelberg and German Cancer Research Center (DKFZ)
Holger Bastians: University Medical Center Göttingen (UMG)
Sergio P. Acebrón: Heidelberg University

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract Human development relies on the correct replication, maintenance and segregation of our genetic blueprints. How these processes are monitored across embryonic lineages, and why genomic mosaicism varies during development remain unknown. Using pluripotent stem cells, we identify that several patterning signals—including WNT, BMP, and FGF—converge into the modulation of DNA replication stress and damage during S-phase, which in turn controls chromosome segregation fidelity in mitosis. We show that the WNT and BMP signals protect from excessive origin firing, DNA damage and chromosome missegregation derived from stalled forks in pluripotency. Cell signalling control of chromosome segregation declines during lineage specification into the three germ layers, but re-emerges in neural progenitors. In particular, we find that the neurogenic factor FGF2 induces DNA replication stress-mediated chromosome missegregation during the onset of neurogenesis, which could provide a rationale for the elevated chromosomal mosaicism of the developing brain. Our results highlight roles for morphogens and cellular identity in genome maintenance that contribute to somatic mosaicism during mammalian development.

Date: 2024
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DOI: 10.1038/s41467-024-51821-9

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