Purine and pyrimidine nucleotides are signaling molecules acting via ionotropic P2X and G-protein-coupled P2Y receptors. Upon release by damaged cells, they accumulate at injury sites and participate to lesion repair. They induce activation, proliferation, migration and differentiation of adult neural progenitor cells (aNPCs) in both neurogenic areas and CNS parenchyma. Parenchymal aNPCs positive for the proteoglycan NG2 (NG2-cells, also known as Oligodendrocyte Precursor Cells, OPCs) express various P2 receptors, including the new P2Y-like GPR17 receptor. We previously reported that GPR17 transiently labels the NG2-cells but it is not present on mature oligodendrocytes and its activation by endogenous ligands promotes, while inhibition by antagonists or silencing RNAs impairs, OPC differentiation. Altogether, these data point at GPR17 as a key regulator of oligodendrocyte maturation. Here, we characterized the mechanisms underlying GPR17 endogenous regulation in primary OPCs, a quite important objective since abnormal GPR17 up-regulation is associated to defective myelination. We have recently shown that, at late differentiation stages, forced GPR17 over-expression, obtained by transfecting a GFP-GPR17 fusion vector, inhibits cell maturation, suggesting that the receptor needs to be down-regulated/desensitized to allow OPC terminal maturation. Physiologically, GPR17 down­regulation may occur through agonist-induced receptor phosphorylation via G-protein coupled receptor kinases (GRKs), which are indeed altered in multiple sclerosis (MS), and are, in turn, controlled by mTOR kinases. Initial in vitro data show that rapamycin, an inhibitor of mTOR kinase, reduces GRK2 levels, with parallel increases in GPR17 expression and strong impairment of OPC maturation, suggesting that dysregulation of these interconnected pathways leading to aberrant GPR17 overexpression may prematurely block OPC maturation. Analysis of GPR17 in vivo in MS models will confirm if the receptor is dysregulated during disease development and will help finding ways to foster myelin repair in demyelinating diseases.

Dysregulation of GPR17, a key receptor involved in NG2 progenitor cells differentiation to mature oligodendrocytes, as a novel potential pathogenetic mechanism in demyelinating diseases / E. Bonfanti, M. Fumagalli, C. Parravicini, S. Daniele, D. Lecca, G. Coppolino, C. Martini, L. Trincavelli, M.P. Abbracchio. ((Intervento presentato al 7. convegno Monotematico SIF “Opportunity and challenges in the pharmacological modulation of neural stem cells" tenutosi a Novara nel 2012.

Dysregulation of GPR17, a key receptor involved in NG2 progenitor cells differentiation to mature oligodendrocytes, as a novel potential pathogenetic mechanism in demyelinating diseases

E. Bonfanti
Primo
;
M. Fumagalli
Secondo
;
C. Parravicini;D. Lecca;G. Coppolino;M.P. Abbracchio
Ultimo
2012

Abstract

Purine and pyrimidine nucleotides are signaling molecules acting via ionotropic P2X and G-protein-coupled P2Y receptors. Upon release by damaged cells, they accumulate at injury sites and participate to lesion repair. They induce activation, proliferation, migration and differentiation of adult neural progenitor cells (aNPCs) in both neurogenic areas and CNS parenchyma. Parenchymal aNPCs positive for the proteoglycan NG2 (NG2-cells, also known as Oligodendrocyte Precursor Cells, OPCs) express various P2 receptors, including the new P2Y-like GPR17 receptor. We previously reported that GPR17 transiently labels the NG2-cells but it is not present on mature oligodendrocytes and its activation by endogenous ligands promotes, while inhibition by antagonists or silencing RNAs impairs, OPC differentiation. Altogether, these data point at GPR17 as a key regulator of oligodendrocyte maturation. Here, we characterized the mechanisms underlying GPR17 endogenous regulation in primary OPCs, a quite important objective since abnormal GPR17 up-regulation is associated to defective myelination. We have recently shown that, at late differentiation stages, forced GPR17 over-expression, obtained by transfecting a GFP-GPR17 fusion vector, inhibits cell maturation, suggesting that the receptor needs to be down-regulated/desensitized to allow OPC terminal maturation. Physiologically, GPR17 down­regulation may occur through agonist-induced receptor phosphorylation via G-protein coupled receptor kinases (GRKs), which are indeed altered in multiple sclerosis (MS), and are, in turn, controlled by mTOR kinases. Initial in vitro data show that rapamycin, an inhibitor of mTOR kinase, reduces GRK2 levels, with parallel increases in GPR17 expression and strong impairment of OPC maturation, suggesting that dysregulation of these interconnected pathways leading to aberrant GPR17 overexpression may prematurely block OPC maturation. Analysis of GPR17 in vivo in MS models will confirm if the receptor is dysregulated during disease development and will help finding ways to foster myelin repair in demyelinating diseases.
Settore BIO/14 - Farmacologia
Dysregulation of GPR17, a key receptor involved in NG2 progenitor cells differentiation to mature oligodendrocytes, as a novel potential pathogenetic mechanism in demyelinating diseases / E. Bonfanti, M. Fumagalli, C. Parravicini, S. Daniele, D. Lecca, G. Coppolino, C. Martini, L. Trincavelli, M.P. Abbracchio. ((Intervento presentato al 7. convegno Monotematico SIF “Opportunity and challenges in the pharmacological modulation of neural stem cells" tenutosi a Novara nel 2012.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/236838
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