Mechanisms of cell shape change in cytokinesis

胞质分裂中细胞形状变化的机制

• 批准号: 10330865
• 负责人: Amy Shaub Maddox
• 金额: $ 38.28万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10330865
• 关键词: Actomyosin; Anaphase; Animals; Behavior; Binding; Biochemical; Biophysics; Blood Cells; Cell Cycle; Cell Shape; Cell division; Cell membrane; Cells; Cellular biology; Chemicals; Chromatin; Collection; Contracts; Coupled; Crosslinker; Cues; Cytokinesis; Cytoskeletal Modeling; Cytoskeleton; Development; Disease; Ensure; F-Actin; Family; Feedback; Fiber; Filament; Generations; Genome; Genome Stability; Grain; Heterogeneity; Lead; Length; Life; Malignant Neoplasms; Mechanics; Meiosis; Methods; Microfilaments; Microscope; Mitotic; Modeling; Motor; Myosin Type II; Neutropenia; Organism; Pattern; Persons; Regulation; Research; Role; Shapes; Signal Transduction; Sum; Testing; Time; Tissues; Work; anillin; base; crosslink; daughter cell; depolymerization; falls; in vivo; innovation; mathematical model; membrane polarity; millisecond; nanoscale; non-muscle myosin; particle; programs; recruit; spatiotemporal; theories; zygote

Project Summary Cytokinesis is the physical division of one cell into two. This final step of the mitotic or meiotic cell cycle partitions the duplicated and segregated genome into topologically distinct daughter cells, and thus ensures genome stability. Cytokinesis is essential for development of the fertilized egg into a multicellular organism, for the replenishment of tissues to compensate for wear and tear, and to avoid diseases of proliferation including cancer and some neutropenias (blood cell disorders). For over a century, people have marveled through the microscope at dividing animal cells, but major questions about the mechanisms of cytokinesis remain. Many of these questions fall under the three Themes of our research program: 1) the cytoskeletal rearrangements that drive contractility, 2) the role of feedback loops in cytokinetic regulation, and 3) modeling the mesoscale. In animal cytokinesis, the cell changes shape as a furrow forms at the cell equator, the region between the two masses of segregated chromatin, as defined by spatio-temporal cues from the anaphase spindle. These cues lead to local activation of RhoA at the plasma membrane. RhoA elicits non-muscle myosin II (NMMII) filament assembly and activity, the generation of long actin filaments (F-actin) by formins, and the cortical recruitment of crosslinkers including anillin and septins. In sum, a circumferential band of cortical actomyosin cytoskeleton assembles and contracts via rearrangement of these cytoskeletal components. F-actin is slid, bundled, crosslinked and coupled to the plasma membrane, polarity sorted, bent, broken and depolymerized. The biophysics of many nano-scale binding partnerships are well studied, but often with sparse collections and without confinement. Since the relative contributions of the many activities listed above to in vivo network dynamics are unknown, our first theme is to define the cytoskeletal remodeling that underlies contractility. After spindle cues pattern the cell equator, both biochemical and mechanical positive feedback boosts these signals. Concurrently, global and localized inhibition via negative feedback limits RhoA activity. Our unpublished observations of contractile oscillations suggest that multiple negative feedback loops coexist. The second theme of our work is the role of feedback loops in cytokinetic regulation. To develop a conceptual model of cytoskeletal rearrangements in cell division, one may imagine the nanoscale molecules and fibers and their millisecond behaviors literally woven into a dynamic material. Like biophysics and cell biology, respectively, mathematical modeling also describes cytoskeletal rearrangements at these two ends of the time- and length scales, via distinct approaches: particle-based modeling (nano- or micro- scale), or continuum mechanics theory (macro-scale). Since both families of approaches have limited ability to coarse grain the mesoscale spatial and temporal heterogeneities of the cytokinetic ring components’ activity states, behaviors, abundances, and combinations, we are working to understand cytokinetic cytoskeletal rearrangements and integrated regulation, by innovating methods to model the mesoscale (theme three).

项目摘要 胞质分裂是一个细胞分裂成两个细胞的物理过程。有丝分裂或减数分裂细胞周期的最后一步 将复制和分离的基因组分割成拓扑上不同的子细胞，从而确保 基因组稳定性胞质分裂是受精卵发育成多细胞生物体所必需的， 组织的补充，以补偿磨损和撕裂，并避免疾病的扩散，包括 癌症和某些贫血症（血细胞疾病）。世纪以来，人们惊叹于 虽然在显微镜下细胞分裂的研究已经取得了进展，但是关于胞质分裂的机制仍然存在着一些重大的问题。许多 这些问题属于我们研究计划的三个主题：1）细胞骨架重排， 驱动收缩性，2）反馈环在细胞动力学调节中的作用，以及3）模拟中尺度。 在动物胞质分裂中，细胞改变形状，在细胞赤道处形成沟， 由来自后期纺锤体的时空线索所定义的两个分离的染色质块。这些 提示导致质膜上RhoA的局部活化。RhoA抑制非肌肉肌球蛋白II（NMMII） 微丝组装和活动，形成蛋白产生的长肌动蛋白丝（F-肌动蛋白），以及皮质 包括苯胺醛和septins的交联剂的补充。总之，皮质肌动球蛋白的环带 细胞骨架通过这些细胞骨架组分的重排组装和收缩。F-肌动蛋白被滑动， 成束、交联和偶联到质膜上，极性分选、弯曲、断裂和解聚。 许多纳米级结合伙伴关系的生物物理学得到了很好的研究，但通常只有稀疏的收集， 没有限制。由于上述许多活动对体内网络的相对贡献 动力学是未知的，我们的第一个主题是定义细胞骨架重塑的基础收缩。 在纺锤体线索图案化细胞赤道后，生物化学和机械正反馈都增强了 这些信号。同时，通过负反馈的全局和局部抑制限制了RhoA活性。我们 未发表的对收缩振荡的观察表明多个负反馈回路共存。的 我们工作的第二个主题是反馈环在细胞动力学调节中的作用。 为了建立一个细胞分裂中细胞骨架重排的概念模型，我们可以想象， 纳米级的分子和纤维，以及它们毫秒级的行为，编织成一种动态的材料。像 生物物理学和细胞生物学，数学建模也描述了细胞骨架重排， 时间和长度尺度的这两端，通过不同的方法：基于粒子的建模（纳米或微米）， 尺度），或连续介质力学理论（宏观尺度）。由于这两种方法的能力有限， 粗颗粒细胞动力学环成分活性的中尺度时空异质性 状态，行为，丰度和组合，我们正在努力了解细胞动力学细胞骨架 通过创新方法建立中尺度模型（专题三），促进区域经济一体化、区域经济一体化和区域经济一体化（专题三）。