Figure 1: SEM image of a differentiating mouse embryonic stem cell, illustrating its highly variable surface topology.
The Diz-Muñoz group studies the crosstalk between mechanical properties of the cell surface and the extracellular environment and intracellular signalling processes that drive morphogenesis and fate in animal cells.
For decades, research aimed at understanding cellular behaviour has largely focused on biochemical reactions. It is well known that binding of soluble extracellular ligands to receptors on the plasma membrane can trigger lipid modifications, protein phosphorylation, and changes in protein localisation. More recently, it has become clear that physical forces also transmit critical information in cells and tissues, where they can regulate a wide variety of cell behaviours, including differentiation, death, and movement, as well as cell shape. At the cell surface, plasma membrane tension has been shown to integrate a wide variety of cell behaviours, ranging from determining leading-edge size to regulating the balance between exocytosis and endocytosis (Sitarska, Diz-Muñoz, Curr Opin Cell Biol 2020).
We are only beginning to understand the many ways in which physical forces, and in particular plasma membrane tension, modulate behaviour at the molecular, cellular, and tissue levels. Current approaches to measure and manipulate forces have important limitations, and new tools and techniques are needed to address these challenges.
Previous and current research
In the past we have focused on the functional roles of membrane tension in controlling leading-edge formation during zebrafish morphogenesis (Diz-Muñoz et al., PLoS Biol 2010) and neutrophil migration (Diz-Muñoz et al., PLoS Biol 2016; Graziano et al., PLoS Biol 2019). This work provided new insights into how cells couple physical forces to intracellular signals and thereby drive essential processes in development and disease.
More recently, we have dissected the individual components of membrane tension and have identified membrane–cortex attachment (MCA) as a key parameter during early differentiation of mouse embryonic stem cells (Bergert et al., Cell Stem Cell 2021). Apart from such intracellular physical parameters, the mechanical properties of the cell’s environment are also well known to be highly relevant in many processes during development and pathology. Within great interdisciplinary collaborations, we have for example shown how asymmetries in extracellular matrix stiffness contribute to organ shape (Crest et al., 2017) or how fibroblast-induced matrix stiffening influences prognosis and therapy in colorectal cancer (Shen et al., Cancer Cell 2020).
Future projects and goals
Our primary interest lies in understanding the reciprocal interactions between physical forces and cellular signalling cascades, with special focus on the mechanics of the cell surface and the adjacent extracellular environment. We focus on three questions in detail:
- How does membrane tension and in particular MCA control the cell surface and how it influences downstream biochemical signalling?
- How does membrane curvature control behaviour, and is it used by cells to read out their membrane tension?
- How do extracellular physical properties couple to cell surface mechanics and cell behaviour?
To investigate these aspects, we develop and apply multiscale and multidisciplinary approaches to precisely quantify and modulate membrane mechanics in an acute manner. This toolbox includes the use of optogenetics, TIRF microscopy, two-photon imaging, FRET sensors, Brillouin and atomic force microscopy, and multi-omics analyses such as proteomics and lipidomics. Using this toolbox, we gain novel mechanistic insights into how membrane tension and tissue elasticity affect cellular signalling and fate specification during morphogenic processes.