Dynamic regulation of integrin activation by intracellular and extracellular signals controls oligodendrocyte morphology

Integrins signal via a process of activation, a conformational change that can be induced either by "outside-in" signals comprising physiological extracellular matrix ligands (mimicked by the pharmacological use of the divalent cation manganese) or "inside-out" signalling molecules such as R-Ras. Increasing levels of outside-in signalling via the laminin receptor α6β1 integrin were found to promote oligodendrocyte processing and myelin sheet formation in culture. Similar results were obtained when inside-out signalling was increased by the expression of a constitutively-active R-Ras. Inhibiting inside-out signalling by using dominant-negative R-Ras reduces processes and myelin sheets; importantly, this can be partially rescued by the co-stimulation of outside-in signalling using manganese.The balance of the equilibrium between active and inactive integrins regulates oligodendrocyte morphology, which is itself regulated by extrinsic and intrinsic cues so providing a mechanism of signal integration. As laminins capable of providing outside-in signals are present on axons at the time of myelination, a mechanism exists by which morphology and myelin generation might be regulated independently in each oligodendrocyte process.The process of myelination in the CNS requires a remarkable morphological transformation by newly-formed oligodendrocytes, with processes contacting and extending along each axon before elaborating a myelin membrane to enwrap the axon multiple times to create a sheath. This differentiation step is tightly controlled, as indicated by the formation of processes each with sufficient membrane for a sheath thickness that has a precise relationship with final axon diameter [1]. In order to ensure that the precise amount of myelin is formed at the right developmental stage and in the correct place, a key component of oligodendrocyte behaviour during myelin formation must be the integration of multiple extrinsic signals at the axon surface along with intrins