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

Yu-Chih Lin,Anja Bufe,Alexander Haas,Sergio P Acebron,Magdalena Hennecke,Holger Bastians,Oksana Voloshanenko,Sabnam Parbin,Michael Boutros,Julia Gross

doi:10.26508/lsa.202000855

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.

Highlights

Wnt signaling pathways play critical roles in various developmental processes during embryogenesis and are important for the maintenance of adult tissue homeostasis [1]
In our work presented here, we show that basal canonical Wnt signaling involving LRP6 and leading to continuous suppression of GSK3β activity is required for the proper regulation of mitotic microtubule dynamics and chromosome segregation
Upon inspection of DKK1treated cells progressing through mitosis by live cell microscopy, we found evidence for chromosome missegregation as indicated by the appearance of lagging chromosomes during anaphase and by generation of micronuclei upon exit from mitosis (Fig S1B)

Summary

Introduction

Wnt signaling pathways play critical roles in various developmental processes during embryogenesis and are important for the maintenance of adult tissue homeostasis [1]. The best characterized Wnt signaling pathway is the so-called canonical pathway that leads to the activation of the transcription factor β-catenin In this pathway, Wnt ligands such as Wnt3a bind to different Frizzled (FZD) receptors and the co-receptors LRP5/6 [7, 8]. The ligand receptor complex clusters together with Dishevelled (Dvl) proteins in LRP6 signalosomes that recruit and inactivate a cytoplasmic destruction complex consisting of adenomatous polyposis coli, AXIN1 and the kinases CK1α and GSK3β [8, 9, 10] The inactivation of this complex prevents the ongoing phosphorylation of the transcription factor β-catenin by CK1α and GSK3β otherwise leading to its degradation by the ubiquitin–proteasome pathway [10, 11, 12]. The secreted protein Dickkopf-1 (DKK1) inhibits canonical Wnt signaling by binding to and inducing the turnover of LRP5/6 coreceptors [13]

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Conclusion