Regulation of microtubule mechanics during epithelial remodeling

• Applicant: Dr. Maja Matis
• Subject Area: Cell Biology ; Developmental Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 553713141

The hallmark of tissue development is collective cell behavior, whereby accurate integration of locally produced mechanical forces into a global tissue force pattern presents one of the principal denominators of cell and tissue shape. Consistently, processes, where this force coordination has gone awry, constitute the cellular basis for numerous diseases, developmental defects, and aberrant wound healing, and have also been associated with several types of cancer. Yet, while the role of actin as a generator of mechanical force is well established, the role of microtubules is only starting to emerge. Microtubules were initially considered to participate in cell mechanics only in a supporting role, contributing, for instance, to the stabilization of the actomyosin or trafficking of adhesion molecules. However, recent work has challenged this view, demonstrating that microtubules can generate protrusive forces crucial for cell mechanics and morphogenetic processes such as tissue bending and extension. As mentioned, we have witnessed a sharp rise in evidence for microtubules contributing to the mechanical state of epithelial tissues over the last decade. However, a crucial element that is frequently overlooked is how spatial and temporal changes in the mechanical properties of microtubules affect cell mechanics. For instance, while current work has established microtubules as force generators, it does not accommodate the fact that biochemical differences between microtubules exist, leading to a temporospatial distribution of mechanical microtubule properties within the same tissue. Here, we aim to unravel the mechanism driving the formation of microtubule subpopulations with distinct mechanical properties within individual cells. To achieve this goal, we developed novel optogenetic tools to control protein activity with high spatiotemporal precision and improved existing biophysical approaches to probe mechanical microtubule properties in vivo. Taking advantage of our interdisciplinary expertise in biophysics, developmental biology and quantitative microscopy, this work will provide crucial novel insights into the role of microtubule mechanics and their regulation during tissue development. Specifically, we will determine the role of (i) different tubulin isotypes and (ii) nucleation factors in controlling mechanical microtubule properties during tissue morphogenesis. Collectively, this project will not only define the molecular mechanisms regulating local microtubule mechanical properties at the cellular level, but will also pinpoint their role in coherent tissue development. Our studies are unparalleled as they shed light on an uncharacterized yet fundamental regulatory network that governs mechanical forces in various developmental and physiological processes.

• DFG Programme: Research Grants