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. In fact, Wnt mediated stabilization of proteins (Wnt/STOP) that involves an LRP6-DVL–dependent signaling cascade is required for proper regulation of mitosis and for faithful chromosome segregation in human somatic cells. We show that inhibition of Wnt/LRP6 signaling causes whole chromosome missegregation and aneuploidy by triggering abnormally increased microtubule growth rates in mitotic spindles, and this is mediated by increased GSK3β activity. We demonstrate that proper mitosis and maintenance of numerical chromosome stability requires continuous basal autocrine Wnt signaling that involves secretion of Wnts. Importantly, we identified Wnt10b as a Wnt ligand required for the maintenance of normal mitotic microtubule dynamics and for proper chromosome segregation. Thus, a self-maintaining Wnt10b-GSK3β–driven cellular machinery ensures the proper execution of mitosis and karyotype stability in human somatic cells.

Significance Wnt signaling plays essential roles in embryonic patterning, stem cell renewal, and cell cycle progression from G1 to S phase via the regulation of β-catenin target genes. Here, we show that Wnt signaling also promotes timely execution of mitosis. We demonstrate that the Wnt signaling transducer Dishevelled recruits the mitotic kinesin KIF2A and mediates its binding to the mitotic spindle. KIF2A is a microtubule depolymerase that controls chromosome alignment and congression during mitosis. Consequently, we found that inhibition of Wnt signaling leads to KIF2A-dependent chromosome congression and alignment delay in somatic and pluripotent stem cells.

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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. This mitotic Wnt signaling functions through Wnt-dependent stabilization of proteins (Wnt/STOP), as well as through components of the LRP6 signalosome. However, the targets and specific functions of mitotic Wnt signaling still remain uncharacterized. Using phosphoproteomics, we identified that Wnt signaling regulates the microtubule depolymerase KIF2A during mitosis. We found that Dishevelled recruits KIF2A via its N-terminal and motor domains, which is further promoted upon LRP6 signalosome formation during mitosis. We show that Wnt signaling modulates KIF2A interaction with PLK1, which is critical for KIF2A localization at the spindle. Accordingly, Wnt signaling promotes chromosome congression and alignment by monitoring KIF2A protein levels at the spindle poles both in somatic cells and in pluripotent stem cells. Our findings highlight a novel function of Wnt signaling during cell division, which could have important implications for genome maintenance, notably in stem cells.SIGNIFICANCEWnt signaling plays essential roles in embryonic patterning, stem cell renewal, and cell cycle progression from G1 to S phase via the regulation of β-catenin target genes. Here, we show that Wnt signaling also promotes faithful execution of mitosis by ensuring chromosome congression and alignment before cell division, including in pluripotent stem cells. We demonstrate that the Wnt signaling transducer Dishevelled recruits the mitotic kinesin KIF2A, and mediates its binding to the spindle. KIF2A is a microtubule depolymerase that controls chromosome alignment and congression during mitosis. Consequently, we found that inhibition of Wnt signaling leads to KIF2A-dependent chromosome congression and alignment defects.