Mechanical control of tissue growth through Hippo signaling
Creators: name: Pan, Yuanwang
Publisher: name: No Publisher Supplied
Year: 2018

description: Tissue growth needs to be properly controlled for organs to reach their correct size and shape, but the mechanisms that control growth during normal development are not fully understood. Recently, mechanical forces have emerged as an important regulator of tissue growth: high cytoskeletal tension enhances tissue growth while low cytoskeletal tension decreases tissue growth. Our lab also discovered that cytoskeletal tension regulates tissue growth through a biomechanical Hippo signaling pathway. However, how mechanical forces are modulated and experienced by cells within developing tissues is not clear. Moreover, whether and how mechanical forces contribute to growth patterns in vivo was not know. To answer these questions, I focused my study on the mechanical feedback model of tissue growth and how mechanical forces contribute to growth control in vivo.    Mechanical feedback. How cells sense mechanical forces and coordinate their growth rates is not clear. One way cells could experience tension in a growing organ was provided by the mechanical feedback model: 1) differential growth rates could lead to local tissue compression as faster-growing cells push against surrounding slower-growing cells, and 2) that this local tissue compression would then decrease growth, thereby restoring even growth rates and minimizing further compression.    I tested the mechanical feedback hypothesis by inducing differential growth in Drosophila wing disc epithelia through distinct approaches. I showed that differential growth triggers a mechanical response that lowers cytoskeletal tension along apical cell junctions within faster-growing cells. This reduced tension modulates a biomechanical Hippo pathway, decreasing recruitment of Ajuba LIM protein and the Hippo pathway kinase Warts to junctions, and reducing the activity of the growth-promoting transcription factor Yorkie. This provides the experimental support and a molecular mechanism for lowering growth rates within faster-growing cells by mechanical feedback. Collaborating with another lab, we also proposed a theoretical model to explain the observed reduction of tension within faster-growing clones, supported through simulations using a modified vertex model. Finally, I found that bypassing mechanical feedback induces tissue distortions and inhomogeneous growth. Thus my research further identifies the roles of mechanical feedback in maintaining tissue shape and controlling patterned growth rates during development.    Growth control in vivo. How tissue growth is modulated in vivo is an important but unsolved question in developmental biology. During Drosophila wing disc development, the cell proliferation rate gradually slows down. But what contributes to this growth reduction is not clear. Recent studies identified that mechanical stress and Hippo signaling are required in organ size control. However, how they are regulated in vivo and their contributions to normal development are largely unknown.     I discovered that the activity of the Hippo signaling transcriptional activator Yorkie gradually decreases in the central region of the developing Drosophila wing disc. Spatial and temporal changes in Yorkie activity can be explained by changes in cytoskeletal tension and biomechanical regulators of Hippo signaling. These changes in cellular biomechanics correlate with changes in cell density, and experimental manipulations of cell density are sufficient to alter biomechanical Hippo signaling and Yorkie activity. I also related the pattern of Yorkie activity in older discs to patterns of cell proliferation. This study shows that spatial differences in Hippo signaling contribute to spatial patterns of growth in vivo, and provides evidence for a contribution of tissue mechanics to regulating patterns of Yorkie activity and growth during wing development.