Abstract
BackgroundMyelination requires precise control of oligodendrocyte morphology and myelin generation at each of the axons contacted by an individual cell. This control must involve the integration of extracellular cues, such as those on the axon surface, with intrinsic developmental programmes. We asked whether integrins represent one class of oligodendrocyte cell-surface receptors able to provide this integration.ResultsIntegrins 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.ConclusionThe 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.
Highlights
Myelination requires precise control of oligodendrocyte morphology and myelin generation at each of the axons contacted by an individual cell
We have shown previously that laminin-2 substrates promote the formation of a differentiated morphological phenotype in oligodendrocytes, as evidenced by increased elaboration of processes and myelin sheets, and that α6 and β1 integrin subunits are found throughout the proc
Because Mn2+ acts directly on the integrin ligand binding domain, we can conclude that the increase in sheet formation reflects a direct effect on the integrin and on the equilibrium between inactive and active integrins, rather than via modulation of separate downstream signalling pathways. These results show that the equilibrium between active and inactive integrins regulates oligodendrocyte morphology and myelin sheet formation
Summary
Myelination requires precise control of oligodendrocyte morphology and myelin generation at each of the axons contacted by an individual cell. 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 intrinsic programmes, such as autonomous developmental timers of differentiation. Since the change of shape can be transmitted across the membrane in either direction, activation can be achieved by so called "inside-out" signals These separate cytoplasmic domains and induce changes in the extracellular ligandbinding site that increase receptor affinity, leading to ligand binding, integrin clustering and signalling. Integrin activation and formation of the signalling complex is regulated by the integration of both extrinsic ligand concentrations and the activity of (intrinsic) 'inside out' signalling pathways
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