Figure 1: Working model of PLD2–TORC2 membrane tension negative feedback loop. This circuit forms a mechanosensory negative feedback loop that acts as a membrane tension homeostat and controls the spatial organisation of actin assembly during neutrophil polarity and movement.
Figure 2: Feedback between curvature and membrane tension.
The Diz-Muñoz group studies the crosstalk between membrane tension and signalling for cell polarity and migration of immune cells and zebrafish mesendodermal precursors.
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 and 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 length cells. 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 focused on the roles mechanics have in zebrafish cell migration and morphogenesis. We demonstrated that increasing cellular blebbing in mesendodermal cells (by reducing membrane tension or increasing intracellular pressure) impairs directed migration. Furthermore, we showed that the ratio of cellular protrusions (blebs to lamellipodia) controls the overall directional persistence of migration in a changing environment, such as 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 (Figure 1). Our work sheds new light on how the plasma membrane integrates physical forces and intracellular signals to organise cell polarity during movement.
Future projects and goals
Our primary interest lies in understanding the reciprocal interactions between physical forces and cellular signalling cascades during the establishment of cell polarity and subsequent cell motility in single cells and intact organisms. We will use a multi-scale and multi-disciplinary approach to develop novel ways to precisely quantify and modulate membrane tension (and membrane tension only) in an acute manner. Combining optogenetics, TIRF microscopy, 2-photon imaging, FRET sensors and atomic force microscopy, we will tackle how membrane tension/curvature affects signalling and vice-versa (Figure 2) to organise cell polarity during movement.