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Abstract

Wnt signaling is crucial for embryonic patterning, the formation of tissues during development, and tissue maintenance in the adult organism. The canonical Wnt pathway induces the transcription of β-catenin target genes, thereby controlling cell cycle progression during G1/S phase, stem cell self-renewal, and stem cell differentiation. However, besides its transcriptional roles, it emerged that Wnt signaling also takes post-translational functions during mitosis. Accordingly, a misregulation of the pathway causes severe mitotic defects, such as chromosome misalignments and chromosome segregation errors, which can ultimately lead to aneuploidy. In this work, I aimed to identify targets of Wnt signaling, which safeguard the correct progression through mitosis, and characterize the underlying molecular mechanisms to explain the emergence of mitotic defects upon Wnt disturbance. First, I revealed that the mitotic kinesin KIF2A is recruited by the Wnt component DVL. DVL localizes KIF2A to the mitotic spindle poles, where it regulates microtubule minus-end dynamics to ensure chromosome alignment before anaphase, both in somatic cells and pluripotent stem cells. This process is supported by the phosphorylation of KIF2A at serine 100 and the interaction with PLK1, which is positively regulated by active Wnt signaling and LRP6 signalosome formation. Second, I verified an S phase-dependent mechanism of Wnt signaling, ensuring the equal segregation of chromosomes in pluripotent stem cells during anaphase. At this, I hypothesize that Wnt signaling contributes to the error-free replication of DNA in S phase, which mediates microtubule plus-end assembly in mitosis, and thereby facilitates faithful chromosome segregation. The validation of both mechanisms in pluripotent stem cells emphasizes their relevance for the understanding of developmental defects, tissue degeneration, and cancer progression, which is often characterized by chromosomal instability. Besides, KIF2A was recruited by DVL also in interphase, indicating that the Wnt-mediated regulation of KIF2A may contribute to processes beyond mitosis, namely ciliogenesis and neurogenesis. Taken together, in my work, I revealed two novel Wnt-dependent mechanisms, which function directly in mitosis or through S phase to control microtubule minus- or plus-end dynamics respectively, ensuring the faithful progression through mitosis, preservation of euploidy, and possibly further post-mitotic processes.