Expression of the new P2Y-like receptor GPR17 during oligodendrocyte precursor cell maturation regulates sensitivity to ATP-induced death.

The P2Y-like receptor GPR17 is expressed by adult neural progenitor cells, suggesting a role in lineage determina- tion. Here, we characterized GPR17 expression and func- tion in mouse cortical primary astrocytes/precursor cell cultures. GPR17 is expressed by a subpopulation of oligo- dendrocyte precursor cells (OPCs), but not by astrocytes. This expression pattern was also con firmed in vivo. In vitro, GPR17 expression wa s m arkedly influenced by culturing conditions. In the presence of growth factors (GFs), no significant GPR17 expression was found. When c ultures were shifted to a differentiating medium, a dra- matic, time-dependent increase in the number of highly branched GPR17-positive cells was observed. Under these conditions, GPR17 was induced in the t otality of O4-posi- tive immature oligodendrocytes. Instead, in cultures origi- nally grown in the absence of GFs, GPR17 was already expressed in morp holo gically more mature OPCs. Shifting of these cultures to differe ntiating cond itions induc ed GPR17 only in a subpopulation of O4-positive cells. Under both culture protocols, appearance of mor e mature CNPase- and MBP-positiv e cells was associated to a pro- gressive loss of GPR17. GPR17 expression also sensitized c ells to adenine nucleotide- induced cytotoxicity, whereas activation with uracil nucleotides promoted differentiation towards a mor e matu re phenotype. We suggest that GFs may keep OPCs in a less differentiated stage by restrain- ing GPR17 expression, and that, under permissive condi- tions, GPR17 contributes to OPCs differentiation. However, upon high extracellular adenine nucleotide concentration s, as during trauma and ischemia, GPR17 sensitizes cells to c ytotoxicity. This double-edged sword role may be exp loited to unveil new therapeutic approaches to ac ute an d chronic brain disorders.