Enhancement of oligodendrocyte remyelination through the ablation of non-muscle myosin II B.

摘要

The myelinating cell of the central nervous system, the oligodendrocyte (OL), undergoes a dramatic change in the organization of its cytoskeleton as it differentiates from an oligodendrocyte precursor cell to a myelin forming OL. This change involves an increase in branching, which is required for the OLs ability to myelinate multiple axons.;Our laboratory has shown that levels of non-muscle myosin II (NMII), a regulator of cytoskeletal contractility, decrease as a function of differentiation and that inhibition of NMII activity increases branching and myelination of OL in coculture with neurons. It was also found that mixed glial cultures derived from NMIIB knockout mice display an increase in the number of mature myelin basic protein expressing OL compared to wild type cultures.;These studies have now been extended to investigate the role of NMIIB ablation in myelin repair following focal demyelination by lysolecithin. To this end, we employed an OL-specific inducible knockout model using a PLP driven promoter in combination with a temporally activated CRE-ER fusion protein. The data indicate that conditional ablation of NMII in adult mouse brain, promotes faster lesion resolution and remyelination when compared to that observed in control brains.;Although several pathways have been implicated in oligodendrocyte morphogenesis, their specific contribution to the regulation of NMII activity has not been directly examined. We tested the hypothesis that the activity of NMII in OPC is controlled by Fyn kinase via downregulation of RhoA-ROCK-NMII phosphorylation. The resulting data confirm the function of NMII as a negative regulator of OL maturation and demonstrate that Fyn kinase downregulates NMII activity thus promoting oligodendrocyte morphological differentiation. Furthermore this study provides a novel target for promoting myelin formation and repair in the adult brain.