Studying mechanisms that spatially control cytokinesis

我的研究计划旨在剖析在细胞分裂中决定分裂平面的机制。胞质分裂是在有丝分裂结束时分离子代细胞的过程，必须以高精度进行，以防止非整倍体和改变细胞命运。经过一个多世纪的研究，很明显，胞质分裂是一个复杂的、强大的过程，由多个鲜为人知的途径控制，在不同的细胞类型中有不同的要求。在动物细胞中，这些途径调节肌动球蛋白收缩环的组装和插入，其时间与染色体分离相协调。目前被广泛接受的模型是，胞质分裂由有丝分裂纺锤体的微管在空间上控制。虽然细胞中央平面(中心纺锤体)的微管提供了刺激收缩环组装和内向的信号，但细胞两极的微管抑制肌动球蛋白。然而，这个模型可能比我们意识到的更复杂：1)我们和其他人所做的研究表明，皮质可以反馈调节纺锤体微管的组织或稳定性，以及2)我们和其他人所做的研究表明，微管独立的机制在空间上调节分裂平面。我们发现，其中一条途径涉及与染色体相关的线索，该线索与有丝分裂纺锤体途径平行发挥作用，以确保分裂平面与它们的分离紧密耦合。这一“染色质途径”可能在极化细胞的分裂中发挥关键作用，因为染色体位于更靠近皮质的部分区域，或者在需要成为多倍体的细胞(如多核细胞)中终止胞质分裂。*我们认为，不同调控胞质分裂的途径的相对“强度”在模型系统和细胞类型之间是不同的。为了测试潜在的细胞质分裂机制，我们将使用两个进化上不同的系统，线虫胚胎和培养的哺乳动物细胞，以及分子、生化和细胞生物学技术来确定：1)皮质和纺锤体微管之间的反馈如何在空间上调节细胞质分裂，以及2)染色质途径如何在空间上调节细胞质分裂。了解胞质分裂如何在不同组织和生物体的不同细胞类型中发挥作用是至关重要的，因为我们之前的大部分知识来自几个癌细胞系或分化前的大型单细胞胚胎。

My research program aims to dissect the mechanisms that determine the cleavage plane in dividing cells. Cytokinesis is a process that occurs at the end of mitosis to separate the daughter cells, and must occur with high precision to prevent aneuploidy and altered cell fate. After more than a century of research, it is clear that cytokinesis is a complex, robust process governed by multiple, poorly-understood pathways with different requirements in different cell types. In animal cells, these pathways regulate the assembly and ingression of an actomyosin contractile ring whose timing is coordinated with chromosome segregation. The current, widely accepted model is that cytokinesis is spatially controlled by the microtubules of the mitotic spindle. While microtubules in the central plane (central spindle) of the cell provide cues that stimulate assembly and ingression of the contractile ring, microtubules in the poles (asters) of the cell inhibit actomyosin. However, this model may be more complex than we realized; 1) studies done by us, and others, have shown that the cortex can feed back to regulate the organization or stability of the spindle microtubules, and 2) studies done by us, and others, have shown that microtubule-independent mechanisms spatially regulate the division plane. We found that one of these pathways involves a cue associated with the chromosomes, which functions in parallel with the mitotic spindle pathways to ensure that the division plane is robustly coupled with their segregation. This 'chromatin pathway' may play a crucial role in the division of polarized cells where chromosomes are positioned closer to part of the cortex, or to abort cytokinesis in cells that need to become polyploidy (e.g. multinucleate).*** We propose that the relative "strengths" of the different pathways regulating cytokinesis vary between model systems and cell types. To test the underlying cytokinesis machinery, we will use two evolutionarily divergent systems, C. elegans embryos and cultured mammalian cells, and molecular, biochemical and cell biological techniques to determine: 1) how feedback between the cortex and spindle microtubules spatially regulates cytokinesis, and 2) how the chromatin pathway spatially regulates cytokinesis. Understanding how cytokinesis works in different cell types in different tissues and organisms is crucial, since the majority of our prior knowledge was derived from a few cancer cell lines or in large, one-cell embryos prior to differentiation.