Sunday, May 18, 2025
5/18/2025
Mechanisms of force production in cytokinesis - Cytokinesis, the physical separation of a mother cell into two daughter cells, occurs by the constriction of a ring of actin filaments, myosin, and other evolutionarily conserved proteins. As cytokinesis is central to the propagation of species, the development of multicellular organisms and critical to the progression of fibrotic diseases and cancer, understanding the mechanisms that govern cytokinesis will broadly impact science and biomedical fields. How the contractile ring generates force remains unknown in part due to our lack of knowledge of its molecular organization, dynamics, and internal mechanics. Our recent progress suggests that the contractile ring produces tension by a mechanism similar to the molecular clutch mechanism of cell migration. According to this a molecular clutch mechanism, membrane-bound protein complexes called nodes engage with the dynamically contracting actin network and transmit the contractile forces to the plasma membrane/cell wall to drive cytokinesis. We will determine the mechanisms that govern force production during cytokinesis with an immediate emphasis on the forces created in the main bundle of actin filaments and how they are transmitted to the plasma membrane/cell wall. We are uniquely positioned to address these questions owing to our innovative combination of genetics, quantitative cell biology, biophysics, single molecule localization microscopy (SMLM), reconstitution assays and simulations. We divide our immediate plans into the different functional layers of the ring: the anchoring, the contractile, and the actin-microtubule crosstalk layers. I- Forces across the anchoring layer. We will determine how nodes respond to mechanical load by measuring their dynamics and molecular organization in constricting contractile rings with a combination of genetics, SMLM methods, tension measurements and NanoTrax. This work will reveal for the first time the mechanical impact of transmitting forces from the contractile actin network to the plasma membrane/cell wall through nodes. II- Forces within the contractile layer. We will determine the dynamic and molecular organization of the actin network in the contractile ring with a combination of genetics, quantitative microscopy, SMLM and biochemical methods. These results will provide the first measurements of actin dynamics and organization within a contractile ring and contribute critical information about the forces that drive constriction. III- Forces in the actin-microtubule crosstalk layer. We will determine how the physical interactions between microtubules and the contractile ring impact cytokinesis with a combination of genetics and quantitative microscopy methods. These results will provide critical knowledge in understanding how actin-microtubule crosstalk contributes to cytokinesis and nuclear positioning during mitosis in fission yeast. This program will determine the foundational mechanisms of tension production in fission yeast cells and will provide the essential steppingstones for our long-term goals to determine the evolutionarily conserved core mechanisms that drive force production and transmission in cytokinesis.
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