The heterogeneous nature of NG2-glia.

In the central nervous system, NG2-glia are the cells responsible for the generation of mature oligodendrocytes during development and adulthood. Some studies could show that NG2-glia can give origin also to astrocytes and neurons, a property that makes them similar to neural stem cells. Beside their important role as progenitors, NG2-glia are believed also to have more functions due to their unique interaction with neurons through synapses. It is however not clear whether these features are common to all NG2-glia or different subpopulations of NG2-glia devoted to different functions exist. Therefore the aim of this review is to highlight the state of the art on NG2-glia heterogeneity from development to adulthood and in different brain areas, and discuss the impact of it on our understanding of the glial neurobiology. This article is part of a Special Issue entitled SI:NG2-glia(Invited only).

NG2-glia and their functions in the central nervous system.

In the central nervous system, NG2-glia represent a neural cell population that is distinct from neurons, astrocytes, and oligodendrocytes. While in the past the main role ascribed to these cells was that of progenitors for oligodendrocytes, in the last years it has become more obvious that they have further functions in the brain. Here, we will discuss some of the most current and highly debated issues regarding NG2-glia: Do these cells represent a heterogeneous population? Can they give rise to different progenies, and does this change under pathological conditions? How do they respond to injury or pathology? What is the role of neurotransmitter signaling between neurons and NG2-glia? We will first give an overview on the developmental origin of NG2-glia, and then discuss whether their distinct properties in different brain regions are the result of environmental influences, or due to intrinsic differences. We will then review and discuss their in vitro differentiation potential and in vivo lineage under physiological and pathological conditions, together with their electrophysiological properties in distinct brain regions and at different developmental stages. Finally, we will focus on their potential to be used as therapeutic targets in demyelinating and neurodegenerative diseases. Therefore, this review article will highlight the importance of NG2-glia not only in the healthy, but also in the diseased brain.

Multiple splice isoforms of proteolipid M6B in neurons and oligodendrocytes.

Proteolipids are abundant integral membrane proteins, initially described as structural proteins of CNS myelin. More recently, two neuronal proteins related to proteolipid protein (PLP), termed M6A and M6B, were identified, suggesting a common function of proteolipids in oligodendrocytes and neurons. We have analyzed the X-linked M6B gene and discovered an unexpected complexity of protein isoforms. Two promoters and alternative exons yield at least eight M6B proteins and polypeptides, differentially expressed in neurons and oligodendrocytes. Six isoforms are tetraspan membrane proteins that differ by highly conserved amino- and carboxy-terminal domains, termed alpha, beta, psi, and omega. In MDCK cells, the beta-domain of M6B stabilizes tetraspan proteolipids at the cell surface, whereas non-beta isoforms are more abundant in intracellular compartments. Cotransfection experiments suggest a physical interaction of M6B and mutant PLP, when retained in the endoplasmic reticulum, that may also contribute to oligodendrocyte dysfunction in Pelizaeus-Merzbacher disease.

Myelin proteolipid proteins promote the interaction of oligodendrocytes and axons.

Although proteolipid protein (PLP) and its DM20 isoform are the major membrane proteins of CNS myelin, their absence causes surprisingly few developmental defects. In comparison, missense mutations of the X-linked Plp gene cause severe dysmyelination. Previous studies have established roles for PLP/DM20 in the formation of the intraperiod line and in maintaining axonal integrity. We now show that a normal number of oligodendrocytes are present in mice lacking PLP/DM20. However, in heterozygous females, which are natural chimeras for X-linked genes, oligodendrocytes lacking PLP/DM20 are in direct competition with wild-type oligodendrocytes that have a distinct advantage. PLP+ oligodendrocytes and PLP+ myelin sheaths make up the greater majority, and this feature is generalised in the CNS throughout life. Moreover, in the absence of PLP/DM20, a proportion of small-diameter axons fails to myelinate, remaining ensheathed but lacking a compact sheath, or show delayed myelination. These findings suggest that PLP/DM20 is also involved in the early stages of axon-oligodendrocyte interaction and wrapping of the axon.