Tuning Microtubule-Actin crosstalk to control Mitotic Fidelity

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Accurate execution of mitosis is pivotal for proper chromosome segregation, the maintenance of chromosomal stability and euploidy. In our previous collaborative work of the lab of Linda Wordeman (Seattle, USA) and Holger Bastians (Göttingen, Germany) we have shown that increased microtubule dynamics in mitosis is a key defect, e.g. seen in human pathologies including cancer, that directly triggers chromosome missegregation and aneuploidy. However, it is unknown how increased microtubule dynamics causes whole chromosome missegregation. In our most recent preliminary work we discovered that even small changes in microtubule dynamics have a significant impact on the proper positioning of the mitotic spindle and this involves a deregulation of the mitotic cortical actin organization. In fact, we found that increased microtubule growth can lead to unscheduled activation of the key actin organizers RAC1 that are known to trigger branched actin polymerization via activation of Arp2/3 actin nucleators. Moreover, we found that increased microtubule dynamics impacts on cortical actin tension that might be mediated by unscheduled RAC1-Arp2/3 activation and leading to spindle mispositioning and whole chromosome missegregation. Based on these new and unexpected findings we hypothesize that increased microtubule dynamics triggers unscheduled hyper-activation of RAC1-Arp2/3 in mitosis to alter cortical actin organization that lowers cortex tension, thereby influencing early spindle positioning and causing chromosome missegregation. For our planned project we will build on the complementary expertise of the Wordeman and Bastians labs to investigate the mechanisms of microtubule dependent RAC1 activation, the impact of unscheduled RAC1-Arp2/3 activation on mitotic cortex organization and tension and the mechanisms of spindle mispositioning and chromosome missegregation in response to increased microtubule dynamics and deregulated mitotic actin cortex organization. We will investigate the microtubule-actin crosstalks in human somatic cells and we will transfer our findings into embryonic systems including Echinoderms and Zebrafish. With this, our studies will address the important and little understood cross-talk mechanisms of the microtubule and actin cytoskeleton in mitosis, which are highly relevant for proper chromosome segregation.