Mechanisms of cell shape change in cytokinesis

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Project Summary Cytokinesis is the physical division of one cell into two. This final step of the mitotic or meiotic cell cycle partitions the duplicated and segregated genome into topologically distinct daughter cells, and thus ensures genome stability. Cytokinesis is essential for development of the fertilized egg into a multicellular organism, for the replenishment of tissues to compensate for wear and tear, and to avoid diseases of proliferation including cancer and some neutropenias (blood cell disorders). For over a century, people have marveled through the microscope at dividing animal cells, but major questions about the mechanisms of cytokinesis remain. Many of these questions fall under the three Themes of our research program: 1) the cytoskeletal rearrangements that drive contractility, 2) the role of feedback loops in cytokinetic regulation, and 3) modeling the mesoscale. In animal cytokinesis, the cell changes shape as a furrow forms at the cell equator, the region between the two masses of segregated chromatin, as defined by spatio-temporal cues from the anaphase spindle. These cues lead to local activation of RhoA at the plasma membrane. RhoA elicits non-muscle myosin II (NMMII) filament assembly and activity, the generation of long actin filaments (F-actin) by formins, and the cortical recruitment of crosslinkers including anillin and septins. In sum, a circumferential band of cortical actomyosin cytoskeleton assembles and contracts via rearrangement of these cytoskeletal components. F-actin is slid, bundled, crosslinked and coupled to the plasma membrane, polarity sorted, bent, broken and depolymerized. The biophysics of many nano-scale binding partnerships are well studied, but often with sparse collections and without confinement. Since the relative contributions of the many activities listed above to in vivo network dynamics are unknown, our first theme is to define the cytoskeletal remodeling that underlies contractility. After spindle cues pattern the cell equator, both biochemical and mechanical positive feedback boosts these signals. Concurrently, global and localized inhibition via negative feedback limits RhoA activity. Our unpublished observations of contractile oscillations suggest that multiple negative feedback loops coexist. The second theme of our work is the role of feedback loops in cytokinetic regulation. To develop a conceptual model of cytoskeletal rearrangements in cell division, one may imagine the nanoscale molecules and fibers and their millisecond behaviors literally woven into a dynamic material. Like biophysics and cell biology, respectively, mathematical modeling also describes cytoskeletal rearrangements at these two ends of the time- and length scales, via distinct approaches: particle-based modeling (nano- or micro- scale), or continuum mechanics theory (macro-scale). Since both families of approaches have limited ability to coarse grain the mesoscale spatial and temporal heterogeneities of the cytokinetic ring components’ activity states, behaviors, abundances, and combinations, we are working to understand cytokinetic cytoskeletal rearrangements and integrated regulation, by innovating methods to model the mesoscale (theme three).