Figure 1: MDCK cells 24h after seeding on a fibronectin pattern. Bright field image (grey), plasma membrane labelled by CAAX.GFP (green), F-actin labelled by lifeact.mCherry (red) and cell nuclei stained with Hoechst 33342 (blue)
The Diz-Muñoz group studies the crosstalk between mechanical properties and signalling processes that drive morphogenesis and fate specification in immune cells, embryonic stem cells and zebrafish embryos.
For decades, research aimed at understanding cellular behaviour has largely focused on biochemical reactions. It is now 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, 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.
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 membrane tension has in zebrafish cell migration and morphogenesis. We demonstrated that increasing cellular blebbing in mesendodermal cells (by reducing membrane tension or increasing intracellular pressure) impairs migration. Furthermore, we showed that the ratio of cellular protrusions (blebs to lamellipodia) controls the overall direction of migration in the developing zebrafish embryo. More recently, we have identified key components of a membrane tension-sensing pathway that controls leading edge formation in neutrophils, and shown how asymmetries in extracellular matrix stiffness contribute to organ shape. Our work provides new insights into how cells couple physical forces to intracellular signals and thereby drive morphogenetic processes.
Future projects and goals
Our primary interest lies in understanding the reciprocal interactions between physical forces and cellular signalling cascades that dictate fate specification, establishment of cell polarity and subsequent cell motility in single cells and intact organisms. To this end, 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, 2-photon imaging, FRET sensors, Brillouin and atomic force microscopy, and multi-omics analyses using 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.