Third party funded individual grant
Start date : 01.01.2014
During the development and lifetime of an animal trillions of cell divisions occur. In the last step of cell division, in a process called cytokinesis, the mother cell splits into two daughter cells. Cytokinesis failure results in tetraploidy and supernumerary centrosomes causing multipolar spindles and oncogenic transformations. During cytokinesis a contractile ring assembles beneath the plasma membrane and its constriction reshapes the mother cell to form two daughter cells. Formation of the contractile ring has to be coordinated with chromosome segregation to ensure that the genomic content is properly partitioned. Synchronization of chromosome segregation with contractile ring formation is ensured by the mitotic spindle, which orchestrates both processes. The mitotic spindle induces contractile ring assembly by activating the small GTPase RhoA at a specific time and in a narrow band around the cell equator. Active RhoA, in turn, directs assembly of the contractile ring. RhoA activity is thought to be specified by two signaling systems. A stimulatory signal is proposed to locally activate RhoA at the cell equator and a not yet identified inhibitory signal is proposed to prevent cortical contractility at the cell poles. How both signals ensure that RhoA is active in a narrow region at the equatorial membrane between the segregating chromosomes is a fundamental but unanswered question in the field of cytokinesis. Small Rho GTPases, like RhoA, are master regulators of the actin cytoskeleton that regulate a vast variety of processes including cell shape, migration, adhesion, and polarity. During all these processes Rho GTPase activity has to be precisely controlled in time and space. Delineating the molecular pathways that govern RhoA GTPase activity during cytokinesis will therefore not only provide fundamental insights into cell division but will also have a profound impact on many other cytoskeleton-related research areas.The goal of the proposed Emmy Noether research group is to elucidate the molecular mechanisms underlying patterning of cortical contractility by the mitotic spindle during cytokinesis. My research will focus on four objectives: (1) to identify the inhibitory signal that prevents contractility at the cell poles, (2) to determine how the stimulatory signal promotes activation of the RhoA at the cell equator, (3) to elucidate the mechanisms of maintaining active RhoA at the cell equator, and (4) to identify new components of the regulatory network controlling cortical patterning during cytokinesis. To study these processes we will develop quantitative imaging assays in C. elegans and in human tissue culture cells that will be complemented with biochemical and genetic approaches. Capitalizing on the advantages of both C. elegans and human cells will allow us to dissect the principles of cortical patterning during cytokinesis.