Tuning Microtubule-Actin crosstalk to control Mitotic Fidelity

有丝分裂的准确执行是正确的染色体分离，染色体稳定性和整倍性的维持的关键。在我们之前与琳达沃德曼（西雅图，美国）和霍尔格巴斯蒂安（哥廷根，德国）实验室的合作工作中，我们已经表明，有丝分裂中微管动力学的增加是一个关键缺陷，例如在包括癌症在内的人类病理学中看到的，它直接触发染色体错误分离和非整倍性。然而，它是未知的增加微管动力学如何导致整个染色体的错误分离。在我们最近的初步工作中，我们发现，即使是微小的微管动力学的变化有显着的影响，有丝分裂纺锤体的正确定位，这涉及到有丝分裂皮层肌动蛋白组织的失调。事实上，我们发现微管生长的增加可以导致关键肌动蛋白组织者RAC 1的非计划性激活，已知RAC 1通过激活Arp 2/3肌动蛋白成核剂来触发分支肌动蛋白聚合。此外，我们发现，增加微管动力学影响皮质肌动蛋白张力，这可能是介导的非计划RAC 1-Arp 2/3激活，并导致纺锤体错位和整个染色体的错误分离。基于这些新的和意想不到的发现，我们假设，增加微管动力学触发非计划性的超激活RAC 1-Arp 2/3在有丝分裂，改变皮质肌动蛋白的组织，降低皮质张力，从而影响早期纺锤体定位，造成染色体误分离。对于我们计划中的项目，我们将建立在沃德曼和巴斯蒂安实验室的互补专业知识，以调查微管依赖的RAC 1激活的机制，非计划RAC 1-Arp 2/3激活对有丝分裂皮层组织和张力的影响，以及纺锤体错位和染色体错误分离的机制，以响应微管动力学增加和有丝分裂肌动蛋白皮层组织失调。我们将研究人类体细胞中的微管-肌动蛋白串扰，并将我们的发现转移到包括棘皮动物和斑马鱼在内的胚胎系统中。有了这个，我们的研究将解决重要的和鲜为人知的串扰机制的微管和肌动蛋白细胞骨架在有丝分裂，这是高度相关的适当的染色体分离。

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.