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Developmental signals control chromosome segregation fidelity during early lineage specification and neurogenesis by modulating replicative stress

ABSTRACT: 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 the modulation of DNA replication stress and damage during S-phase, which in turn controls spindle dynamics and chromosome segregation fidelity in mitosis. We show that patterning signals associated with anteriorisation during mammalian gastrulation increase chromosome missegregation, while the posteriorising signals WNT and BMP protect pluripotent stem cells from excessive origin firing, DNA damage and chromosome missegregation derived from stalled forks. Through epistasis experiments, we find that WNT, BMP and FGF have distinct roles during DNA replication, and demonstrate that WNT/GSK3 signalling sits at the helm of this regulatory cascade. 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. Through ex vivo and in vivo analyses, we also show that FGF and WNT signalling display opposite roles in chromosome segregation fidelity in mouse neural progenitors during the onset of neurogenesis (E14.5), but not during their expansion (E12.5). In particular, we find that the neurogenic factor FGF2 induces DNA replication stress-mediated chromosome missegregation, which could provide a rationale for the elevated chromosomal mosaicism of the developing brain. Our results highlight a role for patterning signals and cellular identity in genome maintenance that contributes to somatic mosaicism during mouse and human early lineage specification and neurogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE271478 | GEO | 2024/07/08

REPOSITORIES: GEO

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Project description:Cardiovascular diseases are a major cause of life-threatening burden around the world. The heart has a very low regeneration capacity and donor organs for transplantation are scarce. Therefore regeneration of lost myocardium with stem cell-derived cardiomyocytes (CMs) provides an attractive strategy for heart repair. Human pluripotent stem cells (hPSCs) can be efficiently differentiated in vitro into CMs but the molecular mechanisms behind this process are still not fully understood. In particular identification of secreted autocrine and/or paracrine factors that function as important extrinsic signals remained elusive because the mass spectrometry (MS)-based identification of secreted proteins from cell culture supernatants is impeded by high levels of albumin present in common differentiation media. Thus we established an albumin-free cardiomyogenic differentiation medium and performed secretomics at seven different time points during in vitro differentiation. This analysis led to the identification of 4832 proteins with 1802 being significantly altered during differentiation and 431 of these were annotated as secreted according to gene ontology. Bioinformatics revealed enrichment of extrinsic Wnt pathway-related proteins 3 days upon induction of differentiation and of extracellular matrix proteins in the resulting CMs. Numerous extrinsic components of Wnt, Activin A, Nodal, TGFβ, BMP or FGF signaling pathways were quantitatively assessed during differentiation. Notably, the abundance of pathway agonists was generally lower compared to the respective antagonists but their curves of progression over timer were rather similar. We hypothesize that Activin A, Nodal and TGFβ signaling are turned down shortly upon initiation of cardiac differentiation whereas BMP signaling is switched on. Wnt and FGF signaling peaks between d0 and d3 of differentiation and interestingly, Activin A and TGFβ signaling seem to be reactivated at the cardiac progenitor stages and/or in early CMs.

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Developmental signals control chromosome segregation fidelity during early lineage specification and neurogenesis by modulating replicative stress

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