Grant: Discovery Grants Program - Individual

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.