Strategies for manipulating integrin activation in oligodendrocytes. Panel A shows the equilibrium between 3 different conformations of integrin; inactive, primed and activated. Only the latter assembles a signalling complex and promotes morphological differentiation of oligodendrocytes, as manifested by complex processes and the formation of myelin sheets. Panel B shows the 2 methods used in this study to promote activation; outside-in signalling using high extracellular matrix (ECM) ligand concentrations or the divalent cation Mn2+ (results in Fig 2), and inside-out signalling using active R-Ras (Fig 3). Panel C illustrates the logic of the experiment shown in Fig 4 to confirm that integrins integrate these extracellular and intracellular cues, showing how outside-in signalling would be predicted to overcome the effects of R-Ras inhibition on oligodendrocyte morphology and myelin sheet formation.