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

Umeå universitet, Institutionen för medicinsk kemi och biofysik Centre for Organismal Studies (COS), Heidelberg University, Heidelberg, Germany Centre for Organismal Studies (COS), Heidelberg University, Heidelberg, Germany Centre for Organismal Studies (COS), Heidelberg University, Heidelberg, Germany Department of Molecular Oncology, Section for Cellular Oncology, University Medical Center Göttingen (UMG), Göttingen, Germany Oncode Institute, Utrecht, Netherlands; Hubrecht Institute, Utrecht, Netherlands; KNAW (Royal Netherlands Academy of Arts and Sciences), Utrecht, Netherlands; University Medical Center Utrecht, Utrecht, Netherlands Oncode Institute, Utrecht, Netherlands; Hubrecht Institute, Utrecht, Netherlands; KNAW (Royal Netherlands Academy of Arts and Sciences), Utrecht, Netherlands; University Medical Center Utrecht, Utrecht, Netherlands Department of Clinical Neurobiology, University Hospital Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany Centre for Organismal Studies (COS), Heidelberg University, Heidelberg, Germany Department of Molecular Oncology, Section for Cellular Oncology, University Medical Center Göttingen (UMG), Göttingen, Germany Genomics Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany Institute of Human Genetics, Heidelberg University, Heidelberg, Germany MRC Laboratory of Molecular Biology, Cambridge, United Kingdom Genomics Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany Centre for Organismal Studies (COS), Heidelberg University, Heidelberg, Germany Schaller Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany Genomics Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany MRC Laboratory of Molecular Biology, Cambridge, United Kingdom Institute of Human Genetics, Heidelberg University, Heidelberg, Germany Nikon Imaging Center at the University of Heidelberg, Bioquant, Heidelberg, Germany Schaller Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany Oncode Institute, Utrecht, Netherlands; Hubrecht Institute, Utrecht, Netherlands; KNAW (Royal Netherlands Academy of Arts and Sciences), Utrecht, Netherlands; University Medical Center Utrecht, Utrecht, Netherlands Centre for Organismal Studies (COS), Heidelberg University, Heidelberg, Germany Department of Clinical Neurobiology, University Hospital Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Molecular Oncology, Section for Cellular Oncology, University Medical Center Göttingen (UMG), Göttingen, Germany Centre for Organismal Studies (COS), Heidelberg University, Heidelberg, Germany 2024

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.

Medical Genetics; Medicinsk genetik; Article in journal; info:eu-repo/semantics/article; text

10.1038.s41467-024-51821-9

Open access content. Open access content
info:eu-repo/semantics/openAccess

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UPE oai:DiVA.org:umu-229381
0000-0002-5657-5626
0000-0003-1708-8259
doi:10.1038/s41467-024-51821-9
PMID 39191776
ISI:001299163800001
Scopus 2-s2.0-85202346452
1457590877

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