Ability Of Oligodendrocytes Research Articles

Purinergic signaling in oligodendrocyte development and function.

Myelin, an insulating membrane that enables rapid action potential propagation, is an essential component of an efficient, functional vertebrate nervous system. Oligodendrocytes, the myelinating glia of the central nervous system (CNS), produce myelin throughout the CNS, which requires continuous proliferation, migration, and differentiation of oligodendrocyte progenitor cells. Because myelination is essential for efficient neurotransmission, researchers hypothesize that neuronal signals may regulate the cascade of events necessary for this process. The ability of oligodendrocytes and oligodendrocyte progenitor cells to detect and respond to neuronal activity is becoming increasingly appreciated, although the specific signals involved are still a matter of debate. Recent evidence from multiple studies points to purinergic signaling as a potential regulator of oligodendrocyte development and differentiation. Adenosine triphosphate (ATP) and its derivatives are potent signaling ligands with receptors expressed on many populations of cells in the nervous system, including cells of the oligodendrocyte lineage. Release of ATP into the extracellular space can initiate a multitude of signaling events, and these downstream signals are specific to the particular purinergic receptor (or receptors) expressed, and whether enzymes are present to hydrolyze ATP to its derivatives adenosine diphosphate and adenosine, each of which can activate their own unique downstream signaling cascades. This review will introduce purinergic signaling in the CNS and discuss evidence for its effects on oligodendrocyte proliferation, differentiation, and myelination. We will review sources of extracellular purines in the nervous system and how changes in purinergic receptor expression may be coupled to oligodendrocyte differentiation. We will also briefly discuss purinergic signaling in injury and diseases of the CNS.

An animal model for late onset chronic demyelination disease caused by failed terminal differentiation of oligodendrocytes

Various animal models are available for studying human multiple sclerosis (MS). Most of them model the initial phase of MS,including the immune-triggered attack of the myelin membrane and/or oligodendrocytes and, occasionally, demonstrate there mission and relapsing phases. However, few mimic the late chronic demyelinating phase. Overexpression of the proteolipid protein gene (Plp) causes a unique demyelinating disorder in mice in which normal-appearing myelin forms early in life and chronic demyelination occurs later. We found that remyelination is severely affected in this late demyelinating phase, but is not caused by deprivation of oligodendrocyte progenitors expressing PDGF receptor alpha (PDGFRa) and Olig2, which are present at an even higher number in the demyelinated white matter of the mutants than in wild-type controls. Furthermore, mature oligodendrocytes containing PLP were observed, but failed to remyelinate. The ability of oligodendrocytes from older transgenic animals to produce a myelin membrane-like structure was not impaired when cultured in vitro, which indicates that the lack of remyelination is not simply caused by changes in the intrinsic properties of the oligodendrocytes. Glial activation also occurred much earlier than active demyelination in mutant mice. Thus, in addition to intrinsic mechanisms, extrinsic mechanisms might also have an important role in defects of remyelination. These features are also observed in patients at a late stage of MS, leading to chronic demyelinating lesions. Thus, this mouse model partly mimics the late stage of MS and can be used to study the cause of inhibition of remyelination.

A role of nerve growth factor in oligodendrocyte growth and differentiation of EAE affected rats.

We have previously shown that the level of nerve growth factor (NGF) undergoes significant changes in the cerebrospinal fluid of patients with Multiple Sclerosis and in the brain of rats affected by Experimental Allergic Encephalomyelitis (EAE). The functional significance of the endogenous disregulation of NGF is not known, though recent studies seem to suggest that NGF might be associated with the ability of oligodendrocytes (OLs) to produce and/or utilise NGF. The aim of the present study was therefore to investigate whether NGF is involved in the development and differentiation of cells of the subventricular zone (SVz) which arbors undifferentiated cells that can give rise to OLs. The results show that NGF injected into the brain of developing rats and of rats affected by EAE is retrogradely transported from the SVz to the brain parenchyma. These findings suggest that during the early phase of brain development and during EAE, NGF, along with other growth factors, is implicated in growth and/or differentiation of OLs and in protecting neuronal injury. The possible functional role of NGF in these events has been discussed.

Glial Transplants: An in vivo Analysis of Extrinsic and Intrinsic Determinants of Dysmyelination in Genetic Variants

Myelination in the CNS depends on the ability of oligodendrocytes (Ols) to efficiently colonize the brain, differentiate, and express a precise balance of specific genes necessary for myelin synthesis. Mutations in these genes produce different types of dysmyelination in animal as in human. Defects in the synthesis of myelin constituents usually lead to mild dysmyelinations. IN contrast, mutations affecting the gene encoding the proteolipid, another major protein of myelin, produce various perturbations of Ols biology suggesting a pleiotropic effect of the gene in the development of the CNS. Studies on expansion of cell population and survival have provided contradictory information on the extrinsic and intrinsic action of the gene on Ols biology. On one hand, in vitro studies using conditioned media as in vivo studies on heterozygotes, and transplantations experiments suggest that excess of programmed cell death in these mutants is ruled out by intrinsic factors which could act during embryonic life. On the other hand, attempts to compensate the gene defect by transgenic correction demonstrate a dominant negative effect of the jp mutation on both survival and functional potential of Ols. Finally, total suppression of PLP gene expression has a restricted effect on myelin structure without excess of cell death. These contradictory results are discussed in the perspective of regulation of cell death by competition for growth factors in limiting amount. The proposed model suggests that this contradiction is only apparent, and that excess of cell death in PLP/DM20 mutant is intrinsically determined by diminished competitivity of the mutant Ols for limited amounts of environmental factors.