Positioning the Plane of Cell Division During Cytokinesis

摘要 成功的细胞分裂需要分裂平面的定位， 被整齐地分隔成两个单独的细胞。此外，在一些细胞类型中，包括干细胞， 分裂面必须与局部细胞命运决定因子相协调。分割平面定位中的误差可 导致染色体获得或丢失，细胞命运决定因素的错误分离，或胞质分裂失败，所有这些 会加速肿瘤的形成在后生动物中，分裂平面是由 有丝分裂后期纺锤体。我们已经发现，两种途径的作用冗余和合作， 定位分割平面。一个途径涉及中央纺锤体，第二个途径涉及星体 微管这两种途径已被证明是不同的机制和遗传。到 了解这些微管为基础的结构调节形成适当的机制， 定位肌动球蛋白为基础的收缩环，我们将使用多学科的战略，结合遗传和 细胞生物学分析C.线虫胚胎和人类细胞，光遗传学，生物化学和活细胞 显像我们将定义导致局部激活RhoA的机制，确定局部区域的 活性RhoA介导收缩环组装，并确定如何激活RhoA激活的全局信号 可以由星状体/中心体形成。这些研究将为深入了解细胞分裂的机制提供帮助 以及涉及通过GTP酶的Rho家族局部调节细胞骨架元件的其它生物过程， 例如细胞极化和细胞迁移。

Abstract 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, mis-segregation 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 optogenetics, biochemistry and live cell imaging. We will define the mechanisms that result in local activation of RhoA, determine how local zones of active RhoA mediate contractile ring assembly, and determine how a global signal to activate RhoA activation can be shaped by asters/centrosomes. These studies 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.