Transient reversion of O4+ Galc− oligodendrocyte progenitor development in response to the phorbol ester TPA

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Abstract
The physiological importance of protein kinase C during oligodendrocyte progenitor maturation was investigated by analyzing the effects of the protein kinase C activator phorbol 12‐myristate 13‐acetate (TPA) on the morphology, proliferation, and differentiation of oligodendrocytes at sequential stages of development. Monoclonal antibodies A2B5 and O4 were used to identify the A2B5+ O4− and the A2B5+ O4+ galactocerebroside− progenitor stages. Anti‐galactocerebroside and anti‐myelin basic protein were used to identify mature, post‐mitotic oligodendrocytes. Proliferation was measured by bromodeoxyuridine incorporation. Within 24 hr after addition, TPA induced a down‐regulation of the O4 antigen in OL progenitors, and an increase of expression of the intermediate filament protein vimentin, leading to a phenotypic reversion from the vimentin− A2B5+ O4+ phenotype to the less mature vimentin+ A2B5+ O4− stage. Concomitantly, TPA induced an increase in the number of bromodeoxyuridine‐labeled oligodendrocyte progenitors and extensive process elongation. The response of O4+ progenitors was transient. Even with continued exposure to TPA, by 4 days after TPA addition the reverted cells ceased proliferation, reacquired O4 immunoreactivity, became vimentin‐negative, and began to express galactocerebroside and myelin basic protein, and to display the complex, highly branched morphology characteristic of terminally differentiated oligodendrocytes. These results indicate that modulation of protein kinase C activity by TPA induces a transient reversion of O4+ progenitors to less mature O4− cells, causing a transient inhibition of terminal differentiation. The relationship of these data to similar responses of the OL lineage to specific growth factors and implications for remyelination after pathologic injury are discussed.