Studying mechanisms that spatially control cytokinesis

我的研究项目旨在剖析细胞分裂过程中决定卵裂平面的机制。细胞质分裂是在有丝分裂结束时分离子细胞的过程，必须高精度地进行，以防止非整倍体和细胞命运的改变。经过一个多世纪的研究，很明显，细胞分裂是一个复杂而强大的过程，由不同细胞类型中不同需求的多种鲜为人知的途径控制。在动物细胞中，这些途径调节肌动球蛋白收缩环的组装和进入，其时间与染色体分离协调。目前广泛接受的模型是，细胞分裂是由有丝分裂纺锤体的微管在空间上控制的。细胞中央平面（中央纺锤体）的微管提供刺激收缩环组装和进入的信号，而细胞两极（中心）的微管则抑制肌动球蛋白。然而，这个模型可能比我们意识到的更复杂；1)我们和其他人的研究表明，皮层可以反馈调节纺锤体微管的组织或稳定性；2)我们和其他人的研究表明，微管独立的机制在空间上调节分裂面。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并行，以确保分裂平面与它们的分离紧密耦合。这种“染色质途径”可能在极化细胞的分裂中起着至关重要的作用，在极化细胞中，染色体的位置更靠近皮层的一部分，或者在需要成为多倍体的细胞中中止细胞质分裂（例如多核）。

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.