The P2Y-like receptor GPR17 as a potential target for the modulation of adult oligodendrogliogenesis

Extracellular nucleotides and their receptors constitute a phylogenetically ancient and universal signalling system that has been recently involved in the self-maintainance, proliferation and terminal differentiation of adult neural precursor cells (NPCs). Thus, it may be possible to enhance the ability of the brain to repair itself via agents that specifically target the purinergic system. In this respect, we have recently reported the characterization of GPR17 a previously orphan G protein-coupled receptor activated by \u201cdanger signals\u201d such as uracil nucleotides and cysteinyl-leukotrienes (cysLTs), whose levels are increased in animals undergoing acute ischemic or traumatic insults to alert local responses to damage and start repair. Analysis of GPR17 in the middle cerebral artery occlusion (MCAo) model of brain focal ischemia in rodents has shown that this receptor is indeed activated/induced in different brain cells according to a precise spatio-temporal pattern after ischemia, to suggest that it may sense the changes in the local nucleotides and cysLTs concentrations and play a role in orchestrating the remodelling and repair of the injured area. In line with these data, we recently showed that GPR17 is a key regulator of myelination. In vitro, GPR17 decorates a subset of slowly proliferating oligodendrocyte precursor cells (OPCs) that also express the markers NG2 and Olig2, whereas it is not expressed in mature myelinating oligodendrocytes. In the adult brain, GPR17 was found on the OPCs of both cortex and spinal cord as well as on corpus callosum immature cells physically associated to or inside myelinating fibers. In developing cortex, GPR17 is transiently upregulated at postnatal day 7 and declines in parallel with myelin maturation. In both developing and adult cortex, actively dividing OPCs never coexpress GPR17, indicating that it is induced at postmitotic stages. Importantly, the in vitro manipulation of GPR17 with its ligands fosters the maturation of OPCs: conversely, GPR17 downregulation is needed to allow their terminal differentiation. Thus, its appropriate manipulation with either pharmacological or biotechnological tools may foster neuro-reparative responses to damage and favour functional recovery not only in stroke, but also after traumatic events and neurodegenerative diseases characterized by demyelinatio