Developmental signals link genome maintenance to stem cell identity. A signalling rheostat controls chromosome segregation fidelity during early lineage specification and neurogenesis by modulating replicative stress

Human development and homeostasis rely on the correct replication, maintenance and segregation of our genetic blueprints. How these intracellular processes are monitored across different human cellular lineages, and why the spatio-temporal distribution of mosaicism varies during development remain unknown. Using human and mouse pluripotent stem cells, we identify that several lineage specification signals –including WNT, BMP and FGF– converge into a signalling “rheostat” that monitors DNA replication stress and damage during S-phase, which in turn controls spindle dynamics and chromosome segregation fidelity in mitosis. Cell signalling control of chromosome segregation declines after pluripotency exit and specification into the three human germ layers, but re-emerges in differentiating neural progenitors. In particular, a tug-of-war between FGF and WNT triggers chromosome missegregation during cortical neurogenesis. Our results highlight moonlighting roles of patterning signals and cell fate in genome maintenance that contribute to somatic mosaicism during human early lineage specification and neurogenesis.