Authors: Sirio Dupont, Leonardo Morsut, Mariaceleste Aragona, Elena Enzo, Stefano Giulitti, Michelangelo Cordenonsi, Francesca Zanconato, Jimmy Le Digabel, Mattia Forcato, Silvio Bicciato, Nicola Elvassore, and Stefano Piccolo
Journal: Nature 474, 179-183 (2011)
In higher organisms, mechanical inputs along with chemical signals are crucial in guiding embryonic development and tissue remodeling, affecting for example stem cell differentiation. As well as these downstream effects, we know many of the key molecular receptors – such as integrins, which allow cells to attach to the extracellular matrix and, when stretched, set off signaling cascades inside the cell.
But much less is understood about how the sensation of mechanical force at the cell surface is transduced into the cell nucleus and regulates the expression pattern of genes involved in cell decision processes. Unlike with chemical signal transduction by receptor tyrosine kinases or GPCRs, the biochemical circuits that connect known mechanical sensors with the known, complex resulting phenotypes are largely unknown
Here, Dupont et al methodically uncovered one signal transduction pathway which mediates transcriptional regulation upon changes in matrix stiffness and cell shape. They first computationally searched for common regulatory factors known to affect genes which are differentially in expressed in mammary epithilial cells grown or more or less stiff substrates. They found that only gene regulation by YAP and TAZ correlated significantly with overexpression on high-stiffness substrates. In the rest of the paper, the authors carefully tested which specific perturbations — including cell shape, tension, cytoskeletal polymerization, total adhesive cell-matrix contact area, etc — lead to YAP / TAZ activation (it’s shape and tension); and whether artificial depletion, or overexpression of an always-active YAP mutant, can mimic the effect of low and high substrate stiffness, respectively, on differentiation (yes).
Not only does this further our understanding of mechanobiology – it also suggests a way for cell engineers to detect and process mechanical signals in synthetic gene circuits.