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ACTOMYO Report Summary

Project ID: 640553
Funded under: H2020-EU.1.1.

Periodic Reporting for period 1 - ACTOMYO (Mechanisms of actomyosin-based contractility during cytokinesis)

Reporting period: 2015-07-01 to 2016-12-31

Summary of the context and overall objectives of the project

The aim of this project is to understand the mechanisms of actomyosin-based contractility during cytokinesis. Cytokinesis completes cell division by physically partitioning the contents of the mother cell into the two daughter cells, ensuring that each daughter cell retains one copy of the replicated genome. In metazoans, cytokinesis is accomplished via the assembly and subsequent constriction of a contractile ring. The contractile ring assembles around the cell equator beneath the plasma membrane after the replicated chromosomes have segregated. Constriction of the ring progressively draws the plasma membrane inwards, closing the gap between the two daughter cells. It is known that the contractile ring is composed of actin and myosin filaments as well as other proteins that regulate actomyosin activity but the inner workings of the ring are still poorly understood. With this work we want to investigate the mechanisms, structure and dynamics of the actomyosin contractile ring in the context of a living organism. The cytokinetic protein machinery is extremely well conserved throughout species and for it being a unique experimental system to conduct investigations on cytokinesis, we use the nematode C. elegans as experimental system. Addressing fundamental questions about cytokinesis and the contractile ring will provide mechanistic insight to understand cell homeostasis and disease. Proper cell division plays an unquestionable role during cell proliferation, development and regeneration of tissues and failure in cytokinesis gives rise to tetraploid cells, which have been postulated to be a critical intermediate in the development of cancer.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Our work has been focused on determining the contribution of branched and non-branched actin filament populations as well as myosin motility and actin filament dynamics to cytokinesis. Our most progress so far has been centered on investigating a robust repair mechanism that is in place during ring constriction to make the ring impervious to discontinuities in its structure. We discovered this phenomenon when we aimed at cutting constricting cytokinetic rings by means of laser microsurgery. Laser cutting of the ring resulted in an immediate snapping event, demonstrating that the ring is under tension. Strikingly, the gap between severed ends was quickly repaired, recovering its original topology and resuming constriction. Surprisingly, many consecutive cuts, which prevented gap repair altogether, still allowed constriction although at a slow rate, which revealed that a continuous contractile ring structure is not a prerequisite for constriction. Mechanical dissection of the ring response to laser cutting indicated that the constricting ring works against tension generated by the remaining cell cortex and dynamic components, such as the increase in surface area of the septum that grows behind the ring as constriction proceeds. Remarkably, after gap repair rings constricted faster than uncut rings and completed cytokinesis in the same time as controls. We attribute this acceleration to the addition of de novo contractile modules to the gap region where the membrane relaxed providing extra room for material addition. In our view, these data provide strong support for the previously proposed model that constriction is powered by a series of contractile units of equal size that locally constrict the plasma membrane at a constant velocity and make additive contributions to the overall constriction velocity.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Our work so far has provided new insights into the cytokinesis process, namely into the stage of ring constriction, the least explored in the field. Importantly, our data show that cytokinesis in vivo is a highly robust process impervious to discontinuities in contractile ring structure. Also, we showed that a continuous ring structure is not a prerequisite for constriction. These are novel ideas in the field that advance our understanding of cytokinesis and constitute important advances to envision and develop models for ring constriction. Understanding the basic mechanisms of cytokinesis is going to prove central to improve diagnosing tools and therapies in disease where this essential cell process is compromised.
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