NG2 cells (polydendrocytes) in brain physiology and repair

Abstract

NG2 cells, also referred to as oligodendrocyte precursor cells (OPCs) or polydendrocytes, represent a major resident glial cell population that is distinct from mature astrocytes, oligodendrocytes, microglia, and neural stem cells and exist throughout the gray and white matter of the developing and mature central nervous system (CNS). While their most established fate is the oligodendrocyte, they retain lineage plasticity in an age- and region-specific manner. During development, they contribute to 36% of protoplasmic astrocytes in the ventral forebrain. Despite intense investigation on the neuronal fate of NG2 cells, there is no definitive evidence that they contribute substantially to the neuronal population. NG2 cells have attributes that suggest that they have functions other than to generate oligodendrocytes, but their exact role in the neural network remains unknown. Under pathological states, NG2 cells not only contribute to myelin repair, but they become activated in response to a wide variety of insults and could play a primary role in pathogenesis.

Keywords: NG2; cell fate; demyelination; myelin; oligodendrocyte; polydendrocyte; subventricular zone.

Figure 1

A schematic showing the fate of NG2 cells throughout development. The middle diagram depicts self-renewing NG2 cells, with a chronological scale across the top. Black arrows indicate the rate of proliferation, which is greatest perinatally. Blue upward arrows indicate oligodendrocyte differentiation, peaking during the third postnatal week. Purple downward arrows indicate astrocyte differentiation, which occurs predominantly before birth and gradually ceases shortly after birth. The thickness of the arrows denotes the extent of differentiation. Modified from Nishiyama (2007).

Figure 2

Lineage-dependent and independent reporter expression in Cre-loxP fate mapping. (A,B) Double labeling for GFP and the neuronal marker NeuN in the neocortex of NG2cre:zeg mice at P14 (A) and P70 (B). NeuN+ GFP+ cells with mature neuronal morphology (arrows) are seen as well as NeuN- GFP+ NG2 cells (arrowheads) in P70 but not in P14 cortex. (C–F) Transfection of zeg reporter plasmid into neuronal precursor cells in NG2cre single transgenic mice. (C) Scheme showing co-transfection of DsRed and zeg plasmid DNA into the lateral ventricles of E13.5 NG2cre single transgenic mice by in utero electroporation and positioning the electrodes to target the dorsal pallium. (D–F) GFP expression in electroporated neurons at P70. All the GFP+ cells were neurons that had been electroporated (DsRed+), and no GFP+ glial cells were detected. This experiment demonstrates that Cre is activated directly in neocortical neurons of NG2cre mice at some point between P14 and P70, leading to GFP expression in neurons. Unlike the case for oligodendrocytes shown in G, there were no GFP+ cells that appeared to be in transition from NG2 cells to neurons. (G) Corpus callosum from P70 NG2creER:YFP mice 14 days after Cre induction with 4-hydroxytamoxifen. A cell that appears to be transitioning from an NG2 cell (NG2+ YFP+) into an NG2- oligodendrocyte (NG2- YFP+) with weak NG2 immunoreactivity in the processes (arrowheads) is seen next to a typical NG2 cell that robustly expresses NG2 (arrow). Inset shows single labeling of the cell marked by arrowhead for NG2.