Centrosomal, Arp2/3 complex-dependent actin assembly is required for proper mitotic spindle formation and chromosome congression

中心体、Arp2/3 复合体依赖性肌动蛋白组装是适当有丝分裂纺锤体形成和染色体大会所必需的

• 批准号: 427436068
• 负责人: Professor Dr. Robert Grosse
• 金额: --
• 依托单位: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/427436068?language=en
• 关键词: Centrosomal; Arp2; complex; dependent; actin

Cytoskeletal crosstalk between actin filaments and microtubules governs the assembly of various cellular structures, such as filopodia or cilia. After disassembly of interphasic structures during mitotic entry, centrosomes operating as microtubule-organizing centers (MTOCs) are of special interest as they propagate the formation of the mitotic spindle, which aligns individual chromosomes to the metaphase plate, a process termed chromosome congression. Here, we aim to investigate actin filament assembly that we find spatially defined at the centrosome contemporaneously with forming spindle microtubules. These actin filaments appear immediately after nuclear envelope breakdown (NEBD) and remain discernable during the course of mitotic spindle formation. Our data show that pharmacological Arp2/3 inhibition at mitotic entry decreases spindle actin and subsequently impairs mitotic spindle formation, which results in severely disorganized chromosome congression and ultimately cell death in non-transformed cells. the aim of this proposal is to further define and elucidate the molecular events and mechanisms during this process. These findings shall provide a better understanding of actin dynamics during cell division and its potential role for the maintenance of genomic integrity during mitosis.

肌动蛋白丝和微管之间的细胞骨架串扰控制着各种细胞结构的组装，如丝状伪足或纤毛。在有丝分裂进入过程中，分裂间期结构解体后，中心体作为微管组织中心（MTOC）发挥作用，因为它们传播有丝分裂纺锤体的形成，使单个染色体与中期板对齐，这一过程称为染色体聚集。在这里，我们的目标是调查肌动蛋白丝组装，我们发现在空间上定义的中心体同时形成纺锤体微管。这些肌动蛋白丝在核膜破裂（NEBD）后立即出现，并在有丝分裂纺锤体形成过程中保持可辨别。我们的数据表明，在有丝分裂进入药理Arp 2/3抑制减少纺锤体肌动蛋白，随后损害有丝分裂纺锤体的形成，这导致严重混乱的染色体congression和最终的细胞死亡在非转化细胞。该提案的目的是进一步定义和阐明这一过程中的分子事件和机制。这些研究结果将提供一个更好的理解肌动蛋白动力学在细胞分裂过程中，其潜在的作用，在有丝分裂过程中的基因组的完整性的维护。