Implications of Olig2 silencing in oligodendrocyte precursor cells

Abstract

Oligodendrocytes (OLs) are the only myelin-forming cells in the central nervous system. Their differentiation from OL precursor cells (OPCs) occurs throughout life and is mediated by numerous intrinsic and extrinsic factors. OL transcription factor 2 (Olig2), a basic helix-loop-helix transcription factor, is one of the intrinsic factors that specify the OL lineage. It is expressed by both OPCs and OLs, and no variant of Olig2 has yet been identified in rodents. Although the function of Olig2 in OL maturation and myelination is still under debate, Olig2 is essential for OPC differentiation in health and disease. Because of its broad expression throughout the OL lineage, Olig2 is often used as a lineage marker. However, in the healthy perinatal and adult brain, a small population of NG2-positive (NG2pos) cells were found to be Olig2-negative (Olig2neg), and stab wound injury increased the population of NG2posOlig2neg cells. NG2 is a protein specifically expressed by OPCs and pericytes in the healthy brain and additionally by microglia after acute brain injury. Therefore, it remained unclear whether these NG2posOlig2neg cells are OPCs or other cell types, such as pericytes or microglia? If these cells are OPCs, are they functionally different from the Olig2pos OPCs? By immunostaining for platelet-derived growth factor receptor alpha (PDGFRα), the established marker of OPCs, we confirmed that a subset of OPCs does indeed not express Olig2. This population of OPCs could be detected throughout life, from the embryonic stage (embryonic day 14.5) to the aged mouse (44 weeks old). Fate mapping studies provided strong evidence that Olig2neg OPCs are derived from pre-existing Olig2pos OPCs (Fang et al., 2023). Therefore, it is conceivable that Olig2neg OPCs do not represent a separate cell type, but rather a distinct functional stage of OPCs in which Olig2 expression is transiently downregulated in response to microenvironmental changes. In other words, OPCs may dynamically up- and downregulate Olig2 expression in response to changes in brain activity.