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

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.

Mitotic WNT: aligning chromosomes through KIF2A.

WNT signaling regulates cell cycle progression and fate determination through β-catenin dependent transcription, and its misregulation is often associated with tumorigenesis. Our recent work demonstrated that basal WNT activity is also required to ensure proper chromosome alignment during mitosis through the regulation of kinesin family member 2A (KIF2A).

Wnt signaling recruits KIF2A to the spindle to ensure chromosome congression and alignment during mitosis.

Canonical Wnt signaling plays critical roles in development and tissue renewal by regulating β-catenin target genes. Recent evidence showed that β-catenin-independent Wnt signaling is also required for faithful execution of mitosis. However, the targets and specific functions of mitotic Wnt signaling still remain uncharacterized.

Wnt10b-GSK3β-dependent Wnt/STOP signaling prevents aneuploidy in human somatic cells.

Wnt signaling is crucial for proper development, tissue homeostasis and cell cycle regulation. A key role of Wnt signaling is the GSK3β-mediated stabilization of β-catenin, which mediates many of the critical roles of Wnt signaling. In addition, it was recently revealed that Wnt signaling can also act independently of β-catenin.