Figure 1

The role of force in myelination. (a) Molecular force generation. Cells bind ECM components through integrin receptors (represented by α and β subunits), thus increasing extracellular adhesion. Integrin activation then triggers signaling cascades involving Fyn kinase, which inhibits RhoA, thus activating ROCK and Myosin IIB. Activated Myosin IIB interacts with actin filaments and creates strong intracellular contractions, which in turn enhances extracellular attachment and possibly mediates cell differentiation. ECM and cytosol color schemes represent the force intensity generated by these molecular events, gray being weakest and red being strongest. (b) Hypothetical effects of extracellular rigidity and intracellular contractions. Optimal myelination conditions require a balance between extracellular forces mediated by matrix rigidity and intracellular forces based on actomyosin contractions (diagonal arrow). A softer matrix inhibits cell differentiation and myelination (shift to the left), which can be counteracted by myosin IIB inhibition (cells return to being balanced). Gliosis, as it occurs in MS, might represent a more rigid matrix (shift to the right), which would require stronger contractile forces to counteract.