Age-Dependent Netrin-1 Signaling Regulates NG2+ Glial Cell Spatial Homeostasis in Normal Adult Gray Matter

Neuron–glial antigen 2-positive (NG2⁺) glial cells are the most proliferative glia type in the adult CNS, and their tile-like arrangement in adult gray matter is under tight regulation. However, little is known about the cues that govern this unique distribution. To this end, using a NG2⁺ glial cell ablation model in mice, we examined the repopulation dynamics of NG2⁺ glial cells in the mature and aged mice gray matter. We found that some resident NG2⁺ glial cells that escaped depletion rapidly enter the cell cycle to repopulate the cortex with altered spatial distribution. We reveal that netrin-1 signaling is involved in the NG2⁺ glial cell early proliferative, late repopulation, and distribution response after ablation in the gray matter. However, ablation of NG2⁺ glial cell in older animals failed to stimulate a similar repopulation response, possibly because of a decrease in the sensitivity to netrin-1. Our findings indicate that endogenous netrin-1 plays a role in NG2⁺ glial cell homeostasis that is distinct from its role in myelination.