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Background: Microglia, an immune cell found exclusively within the CNS, initially develop from haematopoietic stem cell precursors in the yolk sac and colonise all regions of the CNS early in development. Microglia have been demonstrated to play an important role in the development of oligodendrocytes, the myelin producing cells in the CNS, as well as in myelination. Mertk is a receptor expressed on microglia that mediates immunoregulatory functions, including myelin efferocytosis. Findings: Here we demonstrate an unexpected role for Mertk-expressing microglia in both oligodendrogenesis and myelination. The selective depletion of Mertk from microglia resulted in reduced oligodendrocyte production in early development and the generation of pathological myelin. During demyelination, mice deficient in microglial Mertk had thinner myelin and showed signs of impaired OPC differentiation. We established that Mertk signalling inhibition impairs oligodendrocyte repopulation in Xenopus tadpoles following demyelination. Conclusion: These data highlight the importance of microglia in myelination and are the first to identify Mertk as a regulator of oligodendrogenesis and myelin ultrastructure. [ABSTRACT FROM AUTHOR]

Parenchymal oligodendrocyte progenitor cells (pOPCs) are considered the principal cell type responsible for oligodendrogenesis and remyelinaton in demyelinating diseases. Recent studies have demonstrated that neural precursor cells (NPCs) from the adult subven-tricular zone (SVZ) can also generate new oligodendrocytes after demyelination. However, the relative contribution of NPCs versus pOPCs to remyelination is unknown. We used in vivo genetic fate mapping to assess the behavior of each progenitor type within the corpus callosi (CCs) of mice subjected to cuprizone-induced demyelination. Nestin-CreERT2 and Pdgfra-CreERT2 transgenic mice were crossed with fluorescent Cre reporter strains to map the fate of NPCs and pOPCs respectively. In cuprizone-challenged mice, substantial numbers of NPCs migrated into the demyelinated CC and contributed to oligodendrogenesis. This capacity was most prominent in rostral regions adjacent to the SVZ where NPC-derived oligodendrocytes significantly outnumbered those generated from pOPCs. Sixty-two percent of all nodes of Ranvier in this region were flanked by at least one paranode generated from an NPC-derived oligodendrocyte. Remarkably, g-ratios (ratio of the axon diameter to the diameter of the axon plus myelin sheath) of myelinated axons in regions subject to significant NPC-derived remyelination were equivalent to those of unchallenged controls, and immunoelectron microscopy revealed that NPC-derived myelin was significantly thicker than that generated by pOPCs, regardless of axonal caliber. We also demonstrate that a reduced efficiency of remyelination in the caudal CC was associated with long-term impairment in the maturation of oligodendrogenic NPCs but only transient delay in pOPC differentiation. Collectively, our data define a major distinct role for NPCs in remyelination, identifying them as a key target for enhancing myelin repair in demyelinating diseases. [ABSTRACT FROM AUTHOR]

Repair in multiple sclerosis involves remyelination, a process in which axons are provided with a new myelin sheath by new oligodendrocytes. Bone morphogenic proteins (BMPs) are a family of growth factors that have been shown to influence the response of oligodendrocyte progenitor cells (OPCs) in vivo during demyelination and remyelination in the adult brain. We have previously shown that BMP4 infusion increases numbers of OPCs during cuprizone-induced demyelination, while infusion of Noggin, an endogenenous antagonist of BMP4 increases numbers of mature oligodendrocytes and remyelinated axons following recovery. Additional studies have shown that insulin-like growth factor-1 (IGF-1) promotes the survival of OPCs during cuprizone-induced demyelination. Based on these data, we investigated whether myelin repair could be further enhanced by sequential infusion of these agents firstly, BMP4 to increase OPC numbers, followed by either Noggin or IGF-1 to increase the differentiation and survival of the newly generated OPCs. We identified that sequential delivery of BMP4 and IGF-1 during cuprizone challenge increased the number of mature oligodendrocytes and decreased astrocyte numbers following recovery compared with vehicle infused mice, but did not alter remyelination. However, sequential delivery of BMP4 and Noggin during cuprizone challenge did not alter numbers of oligodendrocytes or astrocytes in the corpus callosum compared with vehicle infused mice. Furthermore, electron microscopy analysis revealed no change in average myelin thickness in the corpus callosum between vehicle infused and BMP4-Noggin infused mice. Our results suggest that while single delivery of Noggin or IGF-1 increased the production of mature oligodendrocytes in vivo in the context of demyelination, only Noggin infusion promoted remyelination. Thus, sequential delivery of BMP4 and Noggin or IGF-1 does not further enhance myelin repair above what occurs with delivery of Noggin alone. [ABSTRACT FROM AUTHOR]

Although the transcription factors required for the generation of oligodendrocytes and CNS myelination during development have been relatively well established, it is not known whether continued expression of the same factors is required for the maintenance of myelin in the adult. Here, we use an inducible conditional knock-out strategy to investigate whether continued oligodendrocyte expression of the recently identified transcription factor myelin gene regulatory factor (MRF) is required to maintain the integrity of myelin in the adult CNS. Genetic ablation of MRF in mature oligodendrocytes within the adult CNS resulted in a delayed but severe CNS demyelination, with clinical symptoms beginning at 5 weeks and peaking at 8 weeks after ablation of MRF. This demyelination was accompanied by microglial/macrophage infiltration and axonal damage. Transcripts for myelin genes, such as proteolipid protein, MAG, MBP, and myelin oligodendrocyte glycoprotein, were rapidly downregulated after ablation of MRF, indicating an ongoing requirement for MRF in the expression of these genes. Subsequently, a proportion of the recombined oligodendrocytes undergo apoptosis over a period of weeks. Surviving oligodendrocytes gradually lose the expression of mature markers such as CC1 antigen and their association with myelin, without reexpressing oligodendrocyte progenitor markers or reentering the cell cycle. These results demonstrate that ongoing expression of MRF within the adult CNS is critical to maintain mature oligodendrocyte identity and the integrity of CNS myelin. [ABSTRACT FROM AUTHOR]

The critical role of oligodendrocytes in producing and maintaining myelin that supports rapid axonal conduction in CNS neurons is well established. More recently, additional roles for oligodendrocytes have been posited, including provision of trophic factors and metabolic support for neurons. To investigate the functional consequences of oligodendrocyte loss, we have generated a transgenic mouse model of conditional oligodendrocyte ablation. In this model, oligodendrocytes are rendered selectively sensitive to exogenously administered diphtheria toxin (DT) by targeted expression of the diphtheria toxin receptor in oligodendrocytes. Administration of DT resulted in severe clinical dysfunction with an ascending spastic paralysis ultimately resulting in fatal respiratory impairment within 22 d of DT challenge. Pathologically, at this time point, mice exhibited a loss of ∼26% of oligodendrocyte cell bodies throughout the CNS. Oligodendrocyte cell-body loss was associated with moderate microglial activation, but no widespread myelin degradation. These changes were accompanied with acute axonal injury as characterized by structural and biochemical alterations at nodes of Ranvier and reduced somatosensory-evoked potentials. In summary, we have shown that a death signal initiated within oligodendrocytes results in subcellular changes and loss of key symbiotic interactions between the oligodendrocyte and the axons it ensheaths. This produces profound functional consequences that occur before the removal of the myelin membrane, i.e., in the absence of demyelination. These findings have clear implications for the understanding of the pathogenesis of diseases of the CNS such as multiple sclerosis in which the oligodendrocyte is potentially targeted. [ABSTRACT FROM AUTHOR]