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.

中文翻译：

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Wnt10b-GSK3β 依赖性 Wnt/STOP 信号可防止人类体细胞中的非整倍性。

Wnt 信号传导对于正常发育、组织稳态和细胞周期调节至关重要。Wnt 信号传导的一个关键作用是 GSK3β 介导的 β-连环蛋白的稳定，它介导了 Wnt 信号传导的许多关键作用。此外，最近发现 Wnt 信号传导也可以独立于 β-catenin 起作用。事实上，Wnt 介导的蛋白质稳定 (Wnt/STOP) 涉及 LRP6-DVL 依赖性信号级联反应，是适当调节有丝分裂和在人类体细胞中进行忠实染色体分离所必需的。我们表明抑制 Wnt/LRP6 信号通过触发有丝分裂纺锤体中异常增加的微管生长速率导致整个染色体错误分离和非整倍性，这是由 GSK3β 活性增加介导的。我们证明适当的有丝分裂和数量染色体稳定性的维持需要持续的基础自分泌 Wnt 信号传导，这涉及 Wnts 的分泌。重要的是，我们将 Wnt10b 鉴定为维持正常有丝分裂微管动力学和适当染色体分离所需的 Wnt 配体。因此，自我维持的 Wnt10b-GSK3β 驱动的细胞机制确保了人类体细胞中有丝分裂和核型稳定性的正确执行。