TY - JOUR
T1 - Developmental signals control chromosome segregation fidelity during pluripotency and neurogenesis by modulating replicative stress
AU - de Jaime-Soguero, Anchel
AU - Hattemer, Janina
AU - Bufe, Anja
AU - Haas, Alexander
AU - van den Berg, Jeroen
AU - van Batenburg, Vincent
AU - Das, Biswajit
AU - di Marco, Barbara
AU - Androulaki, Stefania
AU - Böhly, Nicolas
AU - Landry, Jonathan J M
AU - Schoell, Brigitte
AU - Rosa, Viviane S
AU - Villacorta, Laura
AU - Baskan, Yagmur
AU - Trapp, Marleen
AU - Benes, Vladimir
AU - Chabes, Andrei
AU - Shahbazi, Marta
AU - Jauch, Anna
AU - Engel, Ulrike
AU - Patrizi, Annarita
AU - Sotillo, Rocio
AU - van Oudenaarden, Alexander
AU - Bageritz, Josephine
AU - Alfonso, Julieta
AU - Bastians, Holger
AU - Acebrón, Sergio P
N1 - © 2024. The Author(s).
PY - 2024/8/28
Y1 - 2024/8/28
N2 - 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.
AB - 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.
KW - Chromosome Segregation
KW - Neurogenesis/genetics
KW - Animals
KW - DNA Replication
KW - Humans
KW - Mice
KW - DNA Damage
KW - Signal Transduction
KW - Pluripotent Stem Cells/metabolism
KW - Bone Morphogenetic Proteins/metabolism
KW - Fibroblast Growth Factor 2/metabolism
KW - Mitosis
KW - Mosaicism
U2 - 10.1038/s41467-024-51821-9
DO - 10.1038/s41467-024-51821-9
M3 - Article
C2 - 39191776
SN - 2041-1723
VL - 15
SP - 7404
JO - Nature Communications
JF - Nature Communications
IS - 1
ER -