Feel the Force(s)

2019 edition

Fabio Pezzano

Embryonic development has been investigated thoroughly on the basis of genetic and complex biochemical signaling networks. Although they play an essential role in development, mechanical forces are an integral part of the developmental processes. Mechanical forces within a cell and the tissue environment cause changes in size, shape, number, position, and gene expression of cells. Increasing evidence demonstrates that the response to soluble biochemical stimuli is also strongly modified by physical properties of the cellular microenvironment such as adhesive and mechanical forces, thereby affecting cell differentiation (Engler et al., Cell 2006).

In my PhD project, I am investigating the molecular details of how mechanical forces affects cell behavior and its connection to cell differentiation. Zebrafish embryonic stem cells reveal changes in cell mechanical properties during germ layer specification (Krieg et al., NCB 2008). Furthermore, a fast motility switch from a non-motile phenotype to amoeboid migration can be induced by mechanical forces in confined 3D environments. The switch depends on rapid changes in cell mechanics by increasing non-muscle myosin II-dependent actin network contractility (Ruprecht et al., Cell 2015). Increased cortical contractility can spontaneously trigger amoeboid cell polarization with a persistent bleb-like front and retrograde cortical flow.

Having as a readout cellular dynamics and myosin II cortical accumulation, I am currently identifying the mechano- sensor and -transducer leading to this transformation. By providing two different mechanical forces, compression and osmotic shock, I will be able to validate if forces are perceived through the same molecular effectors by the cell. Preliminary results indicate that cells can distinguish the physical perturbation to which they are exposed.

Mechanical force perturbations further induce pronounced changes in sub-cellular protein localization, organelle positioning, nuclear architecture and chromatin condensation. By using a dynamic cell micro-confiner and live-cell superresolution imaging that we are currently implementing in the lab, I will further analyze how cell differentiation couples to mechano-sensing and -transduction in 3D environments.