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

Abstract

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.

Mitotic WNT signalling orchestrates neurogenesis in the developing neocortex

“…Although we have not identified the molecular targets responsible for the decreased asymmetric AP division in DKO embryos, we narrowed down the mechanism to an increase in apical‐basal aMTs, which can directly stabilize the positioning of the mitotic spindle and thus promote symmetric AP division (Mora‐Bermúdez et al , 2014 ). This finding is consistent with recent work in which GSK3 overexpression and inhibition of WNT secretion in HCT116 cells increase MT polymerization rates during mitosis (Lin et al , 2020 ). Interestingly, WNT/STOP inhibition has been also shown to induce mitotic spindle defects and improper chromosome segregation (Stolz et al , 2015 ; Lin et al , 2020 ), pointing towards a more general role of WNT/STOP signalling in promoting mitotic spindle assembly.…”

“…This finding is consistent with recent work in which GSK3 overexpression and inhibition of WNT secretion in HCT116 cells increase MT polymerization rates during mitosis (Lin et al , 2020 ). Interestingly, WNT/STOP inhibition has been also shown to induce mitotic spindle defects and improper chromosome segregation (Stolz et al , 2015 ; Lin et al , 2020 ), pointing towards a more general role of WNT/STOP signalling in promoting mitotic spindle assembly. One possibility is that WNT/STOP signalling modulates MT plus ends, which are key determinants for spindle orientation (Lu & Johnston, 2013 ).…”

CTB-193M12.5 Promotes Hepatocellular Carcinoma Progression via Enhancing NSD1-Mediated WNT10B/Wnt/β-Catenin Signaling Activation

“…WNT10B belongs to the Wnt ligand family, which activates the Wnt/β-catenin signaling. 46 , 47 Therefore, we further explored the potential influences of CTB-193M12.5 on Wnt/β-catenin signaling. Wnt/β-catenin reporter TOPflash was transfected into SNU-398 cells with CTB-193M12.5 overexpression or knockdown, followed by dual luciferase reporter assays, which presented that TOPflash luciferase activity was increased in SNU-398 cells with CTB-193M12.5 overexpression ( Figure 6A ), and while TOPflash luciferase activity was reduced in SNU-398 cells with CTB-193M12.5 knockdown ( Figure 6B ).…”

BMI1 promotes spermatogonial stem cell maintenance by epigenetically repressing Wnt10b/β-catenin signaling

“…Unlike the pro-proliferative activity of Wnt6 in SSCs 28 , we found that Wnt10b exerted an anti-proliferative effect, revealing a novel regulatory mechanism directed by BMI1/Wnt10b/β-catenin signaling in SSCs. Wnt10b has been shown to have roles in the maintenance of normal mitotic microtubule dynamics and appropriate chromosome segregation via the Wnt10b/GSK3β-driven cellular machinery 60 . However, little is known about Wnt10b's role in regulating SSC characteristics.…”