Studying mechanisms that spatially control cytokinesis

我的研究计划旨在剖析决定分裂细胞中分裂平面的机制。胞质分裂是在有丝分裂结束时发生的分离子细胞的过程，并且必须以高精度发生以防止非整倍性和改变的细胞命运。经过超过世纪的研究，很明显，胞质分裂是一个复杂的，强大的过程，由多个，了解不多的途径，在不同的细胞类型有不同的要求。在动物细胞中，这些途径调节肌动球蛋白收缩环的组装和进入，其时间与染色体分离相协调。目前广泛接受的模型是胞质分裂在空间上由有丝分裂纺锤体的微管控制。虽然微管在中央平面（中央纺锤体）的细胞提供线索，刺激组装和收缩环的侵入，微管在极（星状）的细胞抑制肌动球蛋白。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）我们和其他人所做的研究表明，微管独立机制在空间上调节分裂平面。我们发现这些途径之一涉及与染色体相关的线索，其与有丝分裂纺锤体途径平行发挥作用，以确保分裂平面与其分离牢固耦合。这种“染色质途径”可能在极化细胞的分裂中发挥关键作用，其中染色体位于更靠近皮质的部分，或者在需要成为多倍性（例如多核）的细胞中中止胞质分裂。 我们建议，不同的途径调节胞质分裂的相对“强度”不同的模型系统和细胞类型。为了测试潜在的胞质分裂机制，我们将使用两个进化上不同的系统，C。elegans胚胎和培养的哺乳动物细胞，以及分子、生物化学和细胞生物学技术，以确定：1）皮层和纺锤体微管之间的反馈如何在空间上调节胞质分裂，以及2）染色质途径如何在空间上调节胞质分裂。了解胞质分裂如何在不同组织和生物体中的不同细胞类型中发挥作用至关重要，因为我们的大部分先前知识来自少数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.