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


RESULTS
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 alpha6beta1 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.


CONCLUSIONS
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.
Olsen
Inger Marie
IM
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK. Inm@psykiatri.aaa.dk
Ffrench-Constant
Charles
C
D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D002490:Central Nervous System / Q000166:cytology; D017931:DNA Primers; D005786:Gene Expression Regulation; D016023:Integrins / Q000235:genetics*; D009836:Oligodendroglia / Q000166:cytology*; D016548:Prosencephalon / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D017931:DNA Primers; D016023:Integrins; D011993:Recombinant Fusion Proteins