The GPR17 receptor in NG2 expressing cells: Focus on in vivo cell maturation and participation in acute trauma and chronic damage

NG2-expressing cells comprise a population of cycling pre- cursors that can exit the cell cycle and differentiate into mature oligodendrocytes. As a whole, they display heteroge- neous properties and behaviors that remain unresolved at the molecular level, although partly interpretable as dis- tinct maturation stages. To address this issue, we analyzed the expression of the GPR17 receptor, recently shown to decorate NG2-expressing cells and to operate as an early sensor of brain damage, in immature and adult oligoden- drocyte progenitors in the intact brain and after injury. In both the early postnatal and adult cerebral cortex, distinct GPR17 protein localizations and expression levels define different stages of oligodendroglial maturation, ranging from the precursor phase to the premyelinating phenotype. As soon as cells exit mitosis, a fraction of NG2-expressing cells displays accumulation of GPR17 protein in the Golgi apparatus. GPR17 expression is subsequently upregulated and distributed to processes of cells that stop dividing, pro- gressively lose NG2 positivity and assume premyelinating features. Absence of colabeling with mature markers or myelin proteins indicates that GPR17 is downregulated when cells complete their final maturation. BrdU-based fate-mapping demonstrated that a significant fraction of newly generated oligodendrocyte progenitors transiently upregulates GPR17 during maturation. Importantly, we also found that GPR17 does not participate to the early reaction of NG2-expressing cells to damage, while it is induced at postacute stages after injury. These findings identify GPR17 as a marker for progenitor progression within the oligodendroglial lineage and highlight its partici- pation to postacute reactivity of NG2 cells in different lineage comprise an abundant population in the imma- ture and adult central nervous system (CNS) (Butt et al., 2002; Nishiyama et al., 2002). These cells behave as precursors for mature oligodendrocytes in vitro and in vivo, and potentially for astrocytes and neurons (Boda and Buffo, 2010; Nishiyama, 2009; Trotter et al., 2010). Furthermore, they represent the major population of cy- cling cells in the adult nervous tissue (Dawson et al., 2003; Horner et al., 2000; Simon et al., 2011), and respond to injury by increased proliferation (Butt et al., 2002; Simon et al., 2011). Notably, their multiple func- tions also encompass a tight interplay with neurons by synaptic signaling, expression of neurotransmitter receptors and generation of action potentials (Bakiri et al., 2009). However, it is increasingly clear that NG2 positive (1) cells possess heterogeneous properties and behaviors, as indicated by myelination abilities in the adult gray and white matter (Dimou et al., 2008; Rivers et al., 2008), proliferative activity (reviewed in Nishiyama et al., 2009), response to neuronal activity (De Biase et al., 2010) and reaction to injury (Hampton et al., 2004; Lytle et al., 2009). Such diversity can be partly explained by distinct maturation stages (De Biase et al., 2010), but molecular markers are lacking to unambiguously resolve this point. With the aim to gain insights into NG21 cell hetero- geneity, we focused on the G-protein coupled GPR17