Mechanisms of cell shape change in cytokinesis

胞质分裂中细胞形状变化的机制

• 批准号: 10582156
• 负责人: Amy Shaub Maddox
• 金额: $ 24.97万
• 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/10582156
• 关键词: Actomyosin; Anaphase; Animals; Antineoplastic Agents; Behavior; Binding; Biochemical; Biophysics; Blood Cells; Cell Cycle; Cell Shape; Cell division; Cell membrane; Cells; Cellular biology; Chromatin; Collection; Contracts; Coupled; Crosslinker; Cues; Cytokinesis; Cytoskeletal Modeling; Cytoskeleton; Development; Disease; Drug Targeting; Ensure; F-Actin; Family; Feedback; Fiber; Filament; Gastrointestinal tract structure; Generations; Genome; Genome Stability; Grain; Heterogeneity; Lead; Length; Malignant Neoplasms; Mechanics; Meiosis; Methods; Microfilaments; Microscope; Mitotic; Modeling; Myosin Type II; Neutropenia; Organism; Pattern; Persons; Regulation; Research; Role; Shapes; Signal Transduction; Skin; Sum; Time; Tissues; Work; anillin; base; cancer cell; crosslink; daughter cell; depolymerization; falls; in vivo; innovation; mathematical model; membrane polarity; millisecond; nanoscale; non-muscle myosin; particle; programs; recruit; spatiotemporal; theories; tumor; 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 细胞因子是一个细胞分为两个细胞的物理分裂。有丝分裂或减数分裂细胞周期的最后一步 将重复的基因组和隔离的基因组划分为拓扑不同的子细胞，从而确保 基因组稳定性。细胞因子对于将受精鸡蛋发育到多细胞生物中至关重要，因为 补充组织以补偿磨损的磨损，并避免 癌症和某些中性减少症（血细胞疾病）。一个多世纪以来，人们惊叹于 显微镜分裂动物细胞，但有关细胞因子机制的主要问题仍然存在。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 驱动收缩力，2）反馈回路在细胞动力学调节中的作用，以及3）对中尺度进行建模。 在动物的细胞因子中，细胞随着细胞等效器形成沟的形状变化 由后期纺锤体的时空提示定义的两个隔离染色质质量。这些 提示导致质膜上RhoA的局部激活。 Rhoa引起非肌肉肌球蛋白II（NMMII） 细丝组件和活动，形成长肌动蛋白丝（F-肌动蛋白）的产生，皮质产生 招募包括Anillin和Septins在内的交联器。总之，皮质肌动蛋白的圆周带 通过重新排列这些细胞骨架成分的细胞骨架组件和收缩。 F-肌动蛋白是滑动， 捆绑，交联并耦合到质膜，极性分类，弯曲，破碎和解聚。 许多纳米级绑定伙伴关系的生物物理学都很好地研究了，但通常具有稀疏的收藏和 没有监禁。由于上述许多活动对体内网络的相对贡献 动态是未知的，我们的第一个主题是定义构成收缩力的细胞骨架重塑。 主轴提示模式后，细胞平等，生化和机械阳性反馈靴 这些信号。同时，通过负反馈限制了全球和局部抑制作用。我们的 未发表的收缩振荡观察结果表明，多个负面反馈循环并存。这 我们工作的第二个主题是反馈循环在细胞动力学调节中的作用。 为了开发细胞分裂中细胞骨架重排的概念模型，人们可能会想象 纳米级分子和纤维及其毫秒行为实际上编织成动态材料。喜欢 生物物理学和细胞生物学分别是数学建模还描述了细胞骨架重排 时间和长度尺度的这两个末端，通过不同的方法：基于粒子的建模（纳米或微型 - 比例尺）或连续力学理论（宏观尺度）。由于两个方法家族的能力有限 粗粒细胞力学环成分活性的中尺度空间和临时异质性 状态，行为，抽象和组合，我们正在努力理解细胞力学细胞骨架 通过创新方法对中尺度建模（主题三）来重新排列和集成调节。