Abstract
Oligodendrocytes are specialized cells that myelinate axons in the central nervous system. Defects in oligodendrocyte function and failure to form or maintain myelin sheaths can cause a number of neurological disorders. Oligodendrocytes are differentiated from oligodendrocyte progenitor cells (OPCs), which extend several processes that contact, elaborate, and eventually wrap axonal segments to form multilayered myelin sheaths. These processes require extensive changes in the cytoarchitecture and must be regulated by reorganization of the cytoskeleton. Here, we established a simple protocol to isolate and differentiate mouse OPCs, and by using this method, we investigated a role of microtubules (MTs) in oligodendrocyte differentiation. Oligodendrocytes developed a complex network of MTs during differentiation, and treatment of differentiating oligodendrocytes with nanomolar concentrations of MT-targeting agents (MTAs) markedly affected oligodendrocyte survival and differentiation. We found that acute exposure to vincristine and nocodazole at early stages of oligodendrocyte differentiation markedly increased MT arborization and enhanced differentiation, whereas taxol and epothilone B treatment produced opposing outcomes. Furthermore, treatment of myelinating co-cultures of oligodendrocytes and neurons with nanomolar concentrations of MTAs at late stages of oligodendrocyte differentiation induced dysmyelination. Together, these results suggest that MTs play an important role in the survival, differentiation, and myelination of oligodendrocytes.
Highlights
Oligodendrocytes, the myelinating glia in the central nervous system (CNS), enable rapid conduction of electrical impulses and play an essential role in maintaining the long-term integrity of the underlying axons
A recent study has shown that tubulin polymerization promoting protein (TPPP) nucleates MTs in oligodendrocytes and that Tppp knockout mice exhibit hypomyelination and motor coordination defects [11], but how MTs contribute to oligodendrocyte differentiation and myelination remains largely enigmatic
Those MTs are not stabilized in the same way as taxol-stabilized MTs, which might provide an explanation for the opposing effects on oligodendrocyte differentiation
Summary
Oligodendrocytes, the myelinating glia in the central nervous system (CNS), enable rapid conduction of electrical impulses and play an essential role in maintaining the long-term integrity of the underlying axons. Myelinating oligodendrocytes are generated from oligodendrocyte precursor cells (OPCs), which undergo remarkable morphological changes as they differentiate. Transcriptomic analysis of developing oligodendrocytes has revealed that aside from genes encoding myelin proteins, one of the most heavily regulated genes during OPC development are those related to cytoskeleton remodeling [7]. Previous studies have suggested that F-actin assembly mediates the initial protrusion of the motile leading edge during oligodendrocyte differentiation and that subsequent F-actin disassembly facilitates myelin sheet formation at later stages [5,6,10]. A recent study has shown that tubulin polymerization promoting protein (TPPP) nucleates MTs in oligodendrocytes and that Tppp knockout mice exhibit hypomyelination and motor coordination defects [11], but how MTs contribute to oligodendrocyte differentiation and myelination remains largely enigmatic
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