"Control of the Cell Cycle by Mechanical Force"
The mechanisms that determine organ size in correct proportions to the body have long fascinated people. How cell cycle progression of the individual cell is limited when organs reach their correct cellular density remains, however, an unsolved problem at the heart of development and disease. We propose to develop a physico-genetic model for organ size determination: We want to test whether mechanical forces (F) and compression (F per area) are the actual signals of "cell density" in the developing Drosophila melanogaster wing imaginal disc. Cells in this epithelial tissue are coupled to neighbouring cells and the extracellular matrix as they divide in the growing structure. Forces are predicted to arise in the organ due to progressive mitotic division and cell mass/volume increase of daughter cells. Since cells become both subject and object of mechanical pressure, integral feedback by mechanical cues constitutes an intriguing mode for cell proliferation control. With previous tools it has technically not been possible to address the physiological role of mechanical forces in vivo, while computer simulations predict that trans-tissue mechanic coupling can indeed explain uniform cell cycle exit at the correct final organ size. Designing and fabricating biocompatible microengineered devices in our interdisciplinary effort we will exert defined mechanical forces on selected cells within the growing wing imaginal disc. We will, therefore, be in the position to measure the direct impact on cell proliferation. In parallel, we are establishing an equivalent genetic regime with the aim to mimic mechanical force loading on cells in situ. By addressing this question we propose to get insight into the basic molecular paradigms that drive cells in organs to grow with potential for the future understanding of processes involved in cancer initiation and tissue regeneration.