Probing the logic of Hippo-based mechanotransduction with optogenetics

• Applicant: Dr. Kirstin Meyer
• Subject Area: Cell Biology ; Biophysics
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 399327377

Physical forces play a fundamental role for cellular decision-making processes such as proliferation, differentiation, and migration. Perturbation of cellular mechanics causes both developmental disorders and diseases including cancer. Understanding the reciprocal regulation between physical forces and cellular mechanotransducers is therefore important for cell physiology and pathophysiology. Addressing this problem is complicated by the tight coupling of individual sub-processes both within the actin cytoskeleton and in connection with other mechanosensory structures. It requires tools for measuring and manipulating specific, spatially and temporally defined, physical and biochemical properties of the cell. To achieve this, I propose to use optogenetics to probe the logic of actin-dependent mechanotransduction through the Hippo pathway, an important cellular mechanosensor. Overall, I pursue three goals. First, to reveal the logic of signal reception and transmission of the Hippo pathway by controlling the magnitude and dynamics of the mechanical input. Second, to interrogate the relative contributions of mechanics and YAP activation in control of cell fate. And third, to identify the features of the actin cytoskeleton that are sensed by the Hippo pathway. Using a combined confocal and atomic force microscope will allow precise optogenetic manipulations and simultaneous analysis of cell mechanics and Hippo signaling. To probe the significance of the findings in a system that requires Hippo signaling for its physiology, the study will be performed in mouse embryonic stem cells. From the results, I expect fundamental insights into the reciprocal regulation of cell mechanics and behavior.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Orion Weiner