Positioning the plane of cell division during cytokinesis

描述（由申请人提供）：成功的细胞分裂需要定位分裂平面，以便分离的染色体组被干净地划分为两个独立的细胞。此外，在包括干细胞在内的某些细胞类型中，分裂平面必须与局部细胞命运决定因素协调。分裂面定位错误可导致染色体的获得或丢失，细胞命运决定因素的错误分离或细胞质分裂失败，这些都可以加速肿瘤的形成。在后生动物中，分裂平面由有丝分裂后期纺锤体的位置决定。我们发现两条路径是冗余的，并且是合作的来定位除法平面。一条通路涉及中央纺锤体，另一条涉及星状微管。这两种途径已被证明在机械和基因上是不同的。为了了解这些基于微管的结构如何调节基于肌动球蛋白的收缩环的形成，我们将采用多学科策略，将秀丽隐杆线虫胚胎和人类细胞的遗传和细胞生物学分析与生物化学和活细胞成像相结合。我们将解决以下问题：RhoGEF ECT2向中央纺锤体的募集如何导致RhoA的局部激活？细胞动力学支架蛋白anillin是否调节活性RhoA的水平？新型蛋白NOP-1如何介导收缩环组分的组织？高微管密度抑制皮层肌球蛋白募集的分子机制是什么？这些问题的答案将有助于深入了解细胞分裂的机制和其他涉及Rho家族gtpase局部调控细胞骨架元件的生物学过程，如细胞极化和细胞迁移。公共卫生相关性：该项目旨在了解细胞如何繁殖，从而产生两个具有适当细胞嫁妆的子细胞。这一领域的进展可以提高我们对某些癌症如何发展的理解，并可以确定抗肿瘤治疗的靶点。

DESCRIPTION (provided by applicant): Successful cell division requires positioning of the division plane so that the segregated sets of chromosomes are cleanly partitioned into two separate cells. Furthermore, in some cell types, including stem cells, the division plane must be coordinated with localized cell fate determinants. Errors in division plane positioning can cause chromosome gain or loss, missegregation of cell fate determinants, or a failure of cytokinesis, all of which can accelerate tumor formation. In metazoans, the division plane is determined by the position of the mitotic spindle during anaphase. We have found that two pathways act redundantly and cooperatively to position the division plane. One pathway involves the central spindle and the second involves astral microtubules. The two pathways have been demonstrated to be mechanistically and genetically distinct. To understand the mechanism by which these microtubule-based structures regulate formation of a properly positioned actomyosin-based contractile ring, we will use a multidisciplinary strategy, combining genetic and cell biological analysis in C. elegans embryos and human cells, with biochemistry and live cell imaging. We will address the following questions: How does recruitment of the RhoGEF ECT2 to the central spindle result in local activation of RhoA? Does the cytokinetic scaffold protein anillin modulate the levels of active RhoA and how does the novel protein NOP-1 mediate the organization of contractile ring components? Through what molecular mechanism does high microtubule density inhibit cortical recruitment of myosin? The answers to these questions will provide insights into the mechanism of cell division and other biological processes that involve local regulation of cytoskeletal elements by Rho family of GTPases, such as cell polarization and cell migration. PUBLIC HEALTH RELEVANCE: This project is directed towards understanding how cells multiply, leading to the generation of two daughter cells with appropriate cellular dowries. Progress in this area could improve our understanding of how certain cancers develop and could identify targets for anti-tumor therapies.