Department of Physics, University of Colorado, Boulder, CO 80309, USA.; PULS Group, Department of Physics and Cluster of Excellence: Engineering of Advanced Materials, Friedrich-Alexander University Erlangen-Nurnberg, Nagelsbachstr. 49b, Erlangen, Germany.
Department of Physics, University of Colorado, Boulder, CO 80309, USA.
Sci Adv. 2017 Jan 20;3(1):e1601603. doi: 10.1126/sciadv.1601603. eCollection 2017 Jan.
Mitotic spindles use an elegant bipolar architecture to segregate duplicated chromosomes with high fidelity. Bipolar spindles form from a monopolar initial condition; this is the most fundamental construction problem that the spindle must solve. Microtubules, motors, and cross-linkers are important for bipolarity, but the mechanisms necessary and sufficient for spindle assembly remain unknown. We describe a physical model that exhibits de novo bipolar spindle formation. We began with physical properties of fission-yeast spindle pole body size and microtubule number, kinesin-5 motors, kinesin-14 motors, and passive cross-linkers. Our model results agree quantitatively with our experiments in fission yeast, thereby establishing a minimal system with which to interrogate collective self-assembly. By varying the features of our model, we identify a set of functions essential for the generation and stability of spindle bipolarity. When kinesin-5 motors are present, their bidirectionality is essential, but spindles can form in the presence of passive cross-linkers alone. We also identify characteristic failed states of spindle assembly-the persistent monopole, X spindle, separated asters, and short spindle, which are avoided by the creation and maintenance of antiparallel microtubule overlaps. Our model can guide the identification of new, multifaceted strategies to induce mitotic catastrophes; these would constitute novel strategies for cancer chemotherapy.
有丝分裂纺锤体利用一种优雅的双极架构，以高保真度将复制的染色体分离。双极纺锤体由单极初始条件形成；这是纺锤体必须解决的最基本的结构问题。微管、马达和交联剂对于双极性很重要，但对于纺锤体组装所必需和足够的机制仍然未知。我们描述了一个表现出从头开始的双极纺锤体形成的物理模型。我们从裂殖酵母纺锤体极体大小和微管数量、动力蛋白-5 马达、动力蛋白-14 马达和被动交联剂的物理特性开始。我们的模型结果与我们在裂殖酵母中的实验定量一致，从而建立了一个用最小系统来探究集体自组装的系统。通过改变我们模型的特征，我们确定了一组对纺锤体双极性的产生和稳定性至关重要的功能。当存在动力蛋白-5 马达时，其双向性是必需的，但单独存在被动交联剂也可以形成纺锤体。我们还确定了纺锤体组装的特征故障状态——持续的单极、X 纺锤体、分离的星状体和短纺锤体，这些状态可以通过形成和维持平行的微管重叠来避免。我们的模型可以指导识别新的、多方面的诱导有丝分裂灾难的策略；这些将构成癌症化疗的新策略。
