SNX27, a protein involved in down syndrome, regulates GPR17 trafficking and oligodendrocyte differentiation.
The G protein-coupled receptor 17 (GPR17) plays crucial roles in myelination. It is highly expressed during transition of oligodendrocyte progenitor cells to immature oligodendrocytes, but, after this stage, it must be down-regulated to allow generation of mature myelinating cells. After endocytosis, GPR17 is sorted into lysosomes for degradation or recycled to the plasma membrane. Balance between degradation and recycling is important for modulation of receptor levels at the cell surface and thus for the silencing/activation of GPR17-signaling pathways that, in turn, affect oligodendrocyte differentiation. The molecular mechanisms at the basis of these processes are still partially unknown and their characterization will allow a better understanding of myelination and provide cues to interpret the consequences of GPR17 dysfunction in diseases. Here, we demonstrate that the endocytic trafficking of GPR17 is mediated by the interaction of a type I PDZ-binding motif located at the C-terminus of the receptor and SNX27, a recently identified protein of the endosome-associated retromer complex and whose functions in oligodendrocytes have never been studied. SNX27 knock-down significantly reduces GPR17 plasma membrane recycling in differentiating oligodendrocytes while accelerating cells' terminal maturation. Interestingly, trisomy-linked down-regulation of SNX27 expression in the brain of Ts65Dn mice, a model of Down syndrome, correlates with a decrease in GPR17(+) cells and an increase in mature oligodendrocytes, which, however, fail in reaching full maturation, eventually leading to hypomyelination. Our data demonstrate that SNX27 modulates GPR17 plasma membrane recycling and stability, and that disruption of the SNX27/GPR17 interaction might contribute to pathological oligodendrocyte differentiation defects. GLIA 2016. GLIA 2016;64:1437-1460.
CNR - Institute of Neuroscience, Department of Medical Biotechnologies and Translational Medicine (BIOMETRA), Università Degli Studi Di Milano, Milan, Italy.
Veronica
V
Meraviglia
CNR - Institute of Neuroscience, Department of Medical Biotechnologies and Translational Medicine (BIOMETRA), Università Degli Studi Di Milano, Milan, Italy.
Alessandro Francesco
AF
Ulivi
Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission, Department of Pharmacological and Biomolecular Sciences (DiSFeB), Università Degli Studi Di Milano, Milan, Italy.
Marta
M
Boccazzi
CNR - Institute of Neuroscience, Department of Medical Biotechnologies and Translational Medicine (BIOMETRA), Università Degli Studi Di Milano, Milan, Italy.
Fabiola
F
Valenza
CNR - Institute of Neuroscience, Department of Medical Biotechnologies and Translational Medicine (BIOMETRA), Università Degli Studi Di Milano, Milan, Italy.
Alessandra
A
Fratangeli
CNR - Institute of Neuroscience, Department of Medical Biotechnologies and Translational Medicine (BIOMETRA), Università Degli Studi Di Milano, Milan, Italy.
Maria
M
Passafaro
Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission, Department of Pharmacological and Biomolecular Sciences (DiSFeB), Università Degli Studi Di Milano, Milan, Italy.
Davide
D
Lecca
Department of Biomedical and Neuromotor Sciences, Università Degli Studi Di Bologna, Bologna, Italy.
Fiorenza
F
Stagni
Department of Biomedical and Neuromotor Sciences, Università Degli Studi Di Bologna, Bologna, Italy.
Andrea
A
Giacomini
Department of Biomedical and Neuromotor Sciences, Università Degli Studi Di Bologna, Bologna, Italy.
Renata
R
Bartesaghi
Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission, Department of Pharmacological and Biomolecular Sciences (DiSFeB), Università Degli Studi Di Milano, Milan, Italy.
Maria P
MP
Abbracchio
Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission, Department of Pharmacological and Biomolecular Sciences (DiSFeB), Università Degli Studi Di Milano, Milan, Italy.
Stefania
S
Ceruti
CNR - Institute of Neuroscience, Department of Medical Biotechnologies and Translational Medicine (BIOMETRA), Università Degli Studi Di Milano, Milan, Italy.
Patrizia
P
Rosa
D000818:Animals; D001692:Biological Transport / Q000502:physiology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000378:metabolism / Q000473:pathology; D004705:Endocytosis / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D058305:Sorting Nexins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
C121670:GPR17 protein, human; C534979:GPR17 protein, mouse; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; C522885:SNX27 protein, human; C500393:Snx27 protein, mouse; D058305:Sorting Nexins
PDZ-binding motif; PDZ-domain; myelination; receptor endocytosis