Tapping into the glial reservoir: cells committed to remaining uncommitted

Abstract

The development and maturation of the oligodendrocyte requires a series of highly orchestrated events that coordinate the proliferation and differentiation of the oligodendrocyte precursor cell (OPC) as well as the spatiotemporal regulation of myelination. In recent years, widespread interest has been devoted to the therapeutic potential of adult OPCs scattered throughout the central nervous system (CNS). In this review, we highlight molecular mechanisms controlling OPC differentiation during development and the implication of these mechanisms on adult OPCs for remyelination. Cell-autonomous regulators of differentiation and the heterogeneous microenvironment of the developing and the adult CNS may provide coordinated inhibitory cues that ultimately maintain a reservoir of uncommitted glia.

Figure 1.

Developmental origins of OPCs and the final distribution of adult OPCs in the telencephalon. (A) Schematic illustration outlining the origin of OPCs in the telencephalon during development. As indicated by the arrows, OPCs arise first from the medial ganglionic eminence (MGE) at embryonic day 12.5 followed by the lateral ganglionic eminence (LGE) several days later. Cortically derived OPCs appear soon after birth (adapted from Richardson et al., 2006). (B) Despite their spatial and temporal differences in origin, OPCs are evenly distributed throughout the adult brain and are found in regions such as the cortex (CTX), corpus callosum (CC), caudate putamen (CP), and anterior commissure (ACO). PDGFR-α (red) indicates the presence of OPCs. Myelin basic protein (MBP; green) identifies the heavily myelinated white matter tracts. Bar, 500 µm. (C and D) Magnified view of the adult brain, showing the presence of PDGFR-α–expressing adult OPCs dispersed throughout both gray matter, as represented by the cortex, and white matter tracts such as the corpus callosum. Myelin basic protein illustrates the myelinated fibers. Bar, 100 µm.

Figure 2.

Intrinsic and extrinsic mechanisms prevent the differentiation of OPCs to myelinating oligodendrocytes. These mechanisms act during development and in some cases after injury and disease. Solid arrows indicate contact-mediated interactions such as Jagged1 expressed on axons acting through Notch1 on OPCs, leading to the suppression of myelin genes via Hes5. Dashed arrows indicate secreted molecules such as CTGF from the neuron and Wnt from a yet-unidentified source. Although its ligand has not been determined, GPR17 expressed by OPCs is likely sensitive to environmental signals.

Figure 3.

A proposed model for the maintenance of adult OPCs. OPCs (red) reside in a reservoir and are upstream of the dam. They are inhibited from differentiating into oligodendrocytes (green) by several cell-autonomous (intrinsic) and microenvironmental (extrinsic) inhibitory cues. Presumably unidentified inductive cues may act to overcome the inhibitory barrier and allow differentiation to occur.