Deciphering the form and function of novel Piezo1-rich organelles in cell extrusion

Epithelia form barriers essential for organ functions, while their cells turn over at high rates by cell division and death. Here, mechanical forces maintain constant cell numbers, with stretch inducing division and crowding activating extrusion. Cell extrusion drives cell death from sea sponge to humans; hence, identifying its signalling and mechanisms has been essential to understanding how epithelia maintain correct cell numbers and revealed its critical new roles in preventing diseases from cancer to asthma. Piezo1, a mechanosensitive ion channel controls both stretch-activated mitosis and crowding-induced extrusion, yet how it controls both opposing outcomes is mysterious. Interestingly, as cells crowd, Piezo1 shifts from the plasma membrane to large, dynamic organelle-like structures we term “piezosomes” that dissipate into vesicles before a cell extrudes, suggesting they function in extrusion signalling. Using my expertise in quantitative advanced imaging and a novel Piezo1 biosensor I developed, I will use cell culture and zebrafish to i) elucidate the structure of piezosomes and how they form, ii) reveal how they transform into signalling necessary for cell extrusion and iii) identify their composition. Characterisation of this fundamental new component of epithelial cells will be essential to our understanding of epithelial homeostasis and, likely, innate immunity.