SUMMARY The mammalian CNS contains a ubiquitous population of glial progenitors known as NG2+ cells that have the ability to develop into oligodendrocytes and undergo dramatic changes in response to injury and demyelination. Although it has been reported that NG2+ cells are multipotent, their fate in health and disease remains controversial. Here, we generated PDGFαR-CreER transgenic mice and followed their fate in vivo in the developing and adult CNS. These studies revealed that NG2+ cells in the postnatal CNS generate myelinating oligodendrocytes, but not astrocytes or neurons. In regions of neurodegeneration in the spinal cord of ALS mice, NG2+ cells exhibited enhanced proliferation and accelerated differentiation into oligodendrocytes, but remained committed to the oligodendrocyte lineage. These results indicate that NG2+ cells in the normal CNS are oligodendrocyte precursors with restricted lineage potential, and that cell loss and gliosis are not sufficient to alter the lineage potential of these progenitors in ALS mice.

The adult CNS contains an abundant population of oligodendrocyte precursor cells (NG2+ cells) that generate oligodendrocytes and repair myelin, but how these ubiquitous progenitors maintain their density is unknown. Here we generated NG2-mEGFP mice and used in vivo two-photon imaging to study their dynamics in the adult brain. Time-lapse imaging revealed that NG2+ cells in the cortex are highly dynamic; they survey their local environment with motile filopodia, extend growth cones, and continuously migrate. They maintain unique territories through self-avoidance, and NG2+ cell loss through death, differentiation, or ablation triggered rapid migration and proliferation of adjacent cells to restore their density. NG2+ cells recruited to sites of focal CNS injury were similarly replaced by a proliferative burst surrounding the injury site. Thus, homeostatic control of NG2+ cell density through a balance of active growth and self-repulsion ensures that these progenitors are available to replace oligodendrocytes and participate in tissue repair.