Self-organization of spatio-temporal Rho GTPase activity patterns

细胞形态的动态调控在多细胞生物的发育和功能中起着重要作用。例如，细胞的定向迁移对于发育过程中组织的形成和介导有效的免疫反应至关重要。这些过程中的扰动可能导致发育畸形或癌症。细胞如何调节它们的形状还没有得到充分的了解。丝状细胞结构统称为细胞骨架，在这一过程中起着重要作用。这些细丝的动态构建和解构是由信号网络调控的。特定的调节蛋白控制高阶丝状结构的时空组织和相关活动，例如驱动细胞突起或收缩。在我们的初步工作中，我们可以证明细胞的形状是通过信号分子和细胞骨架之间相互作用的自组织过程来调节的。在这个项目中，我们的目标是研究这一过程的潜在分子机制。一个特别的重点将是反馈回路，它产生时空活动模式。特别地，我们观察到亚细胞收缩的振荡和波传播。这些动态的细胞收缩使单个细胞能够探索来自周围环境的机械信号。为了破译潜在的分子机制及其在细胞形状调节中的作用，我们开发了新的基于光的方法，这些方法允许对这些信号网络进行急性的时空扰动。这个项目的另一个目标是细胞收缩和细胞突起的时空协调。在我们的初步工作中，我们惊奇地观察到刺激细胞突出的信号蛋白几乎同时刺激细胞收缩的调节因子。在单个细胞内，随后的突出和收缩过程在时间和空间上分离，从而允许有效的细胞形状变化。耦合这些信号活动的分子机制将在本项目中研究。通过对这些机制的急性扰动，我们将研究这种耦合在单个细胞中细胞突起和收缩协调中的作用及其在动态细胞形状变化中的作用。为了实现更广泛的时空操作，急性信号网络扰动技术将与本项目的主要目标并行进一步发展。基于这个项目的见解，更复杂的过程，例如细胞在正常发育或疾病期间的定向迁移，可以被更具体地研究和定位。

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.