Interactions between oligodendrocyte precursors control the onset of CNS myelination

Abstract

The formation of CNS myelin is dependent on the differentiation of oligodendrocyte precursor cells (OPCs) and oligodendrocyte maturation. How the initiation of myelination is regulated is unclear but it is likely to depend on the development of competence by oligodendrocytes and receptivity by target axons. Here we identify an additional level of control of oligodendrocyte maturation mediated by interactions between the different cellular components of the oligodendrocyte lineage. During development oligodendrocyte precursors mature through a series of stages defined by labeling with monoclonal antibodies A2B5 and O4. Newly differentiated oligodendrocytes begin to express galactocerebroside recognized by O1 antibodies and subsequently mature to myelin basic protein (MBP) positive cells prior to formation of compact myelin. Using an in vitro brain slice culture system that supports robust myelination, the consequences of ablating cells at different stages of the oligodendrocyte lineage on myelination has been assayed. Elimination of all OPC lineage cells through A2B5+, O4+ and O1+ complement mediated cell lysis resulted in a delay in development of MBP cells and myelination. Selective elimination of early OPCs (A2B5+) also unexpectedly resulted in delayed MBP expression compared to controls suggesting early OPCs contribute to the timing of myelination onset. By contrast, elimination of differentiated (O1+) immature oligodendrocytes permanently inhibited the appearance of MBP+ cells suggesting that oligodendrocytes are critical to facilitate the maturation of OPCs. These data illuminate that the presence of intra-lineage feed-forward and feedback cues are important for timely myelination by oligodendrocytes.

Exposure to As, Cd and Pb-mixture impairs myelin and axon development in rat brain, optic nerve and retina

“…Here, we depict a dose-and time-dependent irregularity in the expression levels of MBP, the recognized major myelin indicator (Yang et al, 2011). The anomalous levels of PLP and CNPase, enriched in compacted (Schneider et al, 1995) and un-compacted myelin (Baumann and Pham-Dinh, 2001) respectively, denote a degeneration in the myelin multi-lamellar structure as well as myelin forming oligodendrocytes in cerebral cortex.…”

“…The structural integrity of myelin sheath in brain is dependent on the maturation of oligodendrocytes and axon (Yang et al, 2011), marked majorly by the myelin basic protein (MBP) and neurofilament (NF) respectively (Pons-Vazquez et al, 2011). The proteolipid protein (PLP) is vital for generating the multilayered structure of myelin Toxicology and Applied Pharmacology xxx (2013) xxx-xxx (Fulton et al, 2010).…”

An elevated level of circulating galanin promotes developmental expression of myelin basic protein in the mouse brain

“…Previous studies have shown that the final number of mature oligodendrocytes will remain the same even when the number of OPCs increases (Yang et al, 2011). This behavior may be the result of several different regulatory mechanisms in the brain, including apoptotic pathways triggered by a high OPC density, the inhibition of OPC proliferation when a critical number of cells has been reached or even competition between early and late OPCs that results in the survival of one group over the other (Yang et al, 2011). These potential mechanisms suggest that changes in OPC proliferation may not be observable even when other changes are observed in this mouse model.…”

“…However, there do appear to be changes in the OPC maturation rate, based on the earlier increase of MBP (characteristic of mature OLs) in day 10 TG mice. Previous studies have shown that the final number of mature oligodendrocytes will remain the same even when the number of OPCs increases (Yang et al, 2011). This behavior may be the result of several different regulatory mechanisms in the brain, including apoptotic pathways triggered by a high OPC density, the inhibition of OPC proliferation when a critical number of cells has been reached or even competition between early and late OPCs that results in the survival of one group over the other (Yang et al, 2011).…”

Regulation of human glia by multiple sclerosis disease modifying therapies

“…To be considered in this review is the capacity of current therapeutic agents to promote these functions or protect the cells from putative immune-mediated injury. Remyelination is considered to be dependent on recruitment and differentiation of OPCs [12].…”