Self-organization of spatio-temporal Rho GTPase activity patterns

细胞形态的动态调节在多细胞生物体的发育和功能中起着重要作用。例如，细胞的定向迁移对于形成发育过程中的组织和调节有效的免疫反应是必不可少的。这些过程中的干扰可能会导致发育畸形或癌症。细胞是如何调节它们的形状的，目前还不够清楚。丝状细胞结构统称为细胞骨架，在这一过程中发挥着重要作用。这些细丝的动态构建和解构受信号网络的调节。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的相互作用通过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。特别关注的将是产生时空活动模式的反馈回路。特别是，我们观察到了亚细胞收缩的振荡和波的传播。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控中的作用，我们开发了基于光的新方法，允许这些信号网络发生剧烈的时空扰动。该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，我们令人惊讶地观察到，刺激细胞突起的信号蛋白几乎同时刺激细胞收缩的调节。随后的突起和收缩过程在单个细胞内在时间和空间上分离，从而允许有效的细胞形状改变。这个项目将研究耦合这些信号活动的分子机制。通过对这些机制的剧烈扰动，我们将研究这种耦合对单个细胞中细胞突起和收缩的协调作用，以及它对细胞形状动态变化的作用。为了能够实现更广泛的时空操纵，针对急性信号网络扰动的技术将与该项目的主要目标并行地进一步开发。基于该项目的见解，可以更具体地研究和针对更复杂的过程，例如在正常发育期间或疾病期间的细胞定向迁移。

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.