Self-organization of spatio-temporal Rho GTPase activity patterns

• Applicant: Privatdozent Dr. Leif Dehmelt
• Subject Area: Cell Biology ; Biophysics
• Term: from 2017 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 381735331

The dynamic regulation of the cell shape plays an important role in the development and function of multicellular organisms. For example, the directional migration of cells is essential for shaping tissues during development and for mediating an effective immune response. Perturbations in those processes can lead to developmental malformations or cancer. How cells regulate their shape is not yet sufficiently understood. Filamentous cell structures that are collectively called the cytoskeleton play an important role in this process. The dynamic construction and deconstruction of those filaments is regulated by signal networks. Specific regulatory proteins control the spatio-temporal organization of higher-order filamentous structures and associated activities that for example drive cell protrusion or contraction.In our preliminary work, we could show that the shape of cells is regulated via a self-organizing process by reciprocal interactions between signal molecules and the cytoskeleton. In this project, we aim to study the underlying molecular mechanisms of this process. A special focus will be on feedback loops, which generate spatio-temporal activity patterns. In particular, we observed oscillations and wave propagation of sub-cellular contraction. Those dynamic cell contractions enable single cells to explore mechanical signals from their surroundings. To decipher the underlying molecular mechanisms and their role in the regulation of cell shape, we developed novel, light-based methods, which allow acute, spatio-temporal perturbations of those signal networks.Another goal of this project is the spatio-temporal coordination of cell contraction and cell protrusion. In our preliminary work, we surprisingly observed that signal proteins that stimulate cell protrusion almost simultaneously stimulate regulators of cell contraction. The subsequent protrusion and contraction processes separate in time and space within a single cell and thereby allow effective cell shape changes. The molecular mechanisms that couple those signal activities will be studied in this project. Via acute perturbation of those mechanisms, we will investigate the role of this coupling for the coordination of cell protrusion and contraction in individual cells and its role for dynamic cell shape changes. To enable a broader spectrum of spatio-temporal manipulations, the techniques for acute signal network perturbations will be further developed in parallel to the main goals of this project.Based on the insights of this project, more complex processes, for example in the directional migration of cells during normal development or during diseases, could be studied and targeted more specifically.

• DFG Programme: Research Grants