Role of the P2Y-like receptor in neural precursor cells

Three main findings have recently opened new opportunities for repairing the adult brain in both acute (trauma, stroke) and chronic disorders, as Alzheimer's, Parkinson's diseases and multiple sclerosis. First, the generation of new neurons and new glia (neurogenesis) continues throughout life. Second, adult neurogenesis does not only occur in “neurogenic niches", but the entire brain's parenchyma is full of quiescent progenitors that are activated after injury. Two main types of such cells have been identified: (i) proliferating reactive astrocytes; (ii) NG2-positive polydendrocytes, that, under some conditions, can generate oligodendrocytes, neurons and astrocytes (Nishiyama et al., Nat Rev Neurosci 2009, 10:9-22). Third, various types of P2Y receptors are present on polydendrocytes, including the P2Y-like receptor GPR17. Specifically, GPR17 decorates two subsets of slowly proliferating NG2-expressing cells: (i) morphologically immature cells expressing early proteins like Olig2 and PDGF receptor-α, and (ii) ramified pre-oligodendrocytes already expressing more mature factors, like O4 and O1. Of note, activation of GPR17 by its endogenous ligands such as uracil nucleotides (Ciana et al., EMBO J 2006, 25:4615-27; Benned-Jensen and Rosenkilde, Br J Pharmacol 2010, 159:1092-105) promotes cell differentiation towards mature oligodendrocytes, while its inhibition by receptor antagonists or small interfering RNAs impairs the differentiating program of these cells (Fumagalli et al., J Biol Chem 2011, 286:10593-604). GPR17 is thus a new key player in polydendrocytes maturation. These data may have implications for the in vivo behaviour of adult NG2-positive cells and point to uracil nucleotides and cysLTs as main extrinsic local regulators of these cells under physiological conditions and during myelin repair.