SNX27 regulates GPR17 recycling and the kinetics of oligodendrocyte differentiation

Endocytosis has important role in regulating the levels of proteins and receptors at the plasma membrane. We have recently characterized the endocytic pathways of the P2Y-like receptor GPR17, that has been shown to be an intrinsic regulator of oligodendrocyte maturation. GPR17 is up-regulated during transition of oligodendrocyte precursor cells to pre-myelinating oligodendrocytes, but must be down-regulated to allow oligodendrocyte complete maturation. Like many other GPCRs, GPR17 undergoes to constitutive or stimulated endocytosis. After internalization, it can be sorted to lysosome for degradation or to recycling, which occurs through the Rab4-associated pathway. The balance between degradation and recycling modulates the levels of GPR17 at the membrane and its signalling, that may, in turn, affect OPC differentiation. Thus, in search for the mechanisms that may regulate GPR17 endosomal sorting, we focused our attention on the C-terminal class I PDZ-binding motif present in its sequence and we demonstrated that site-directed mutagenesis of this motif affects the receptor intracellular trafficking. Furthermore we showed that sorting nexin 27 (SNX27), a recently identified protein of the retromer complex, interacts with the PDZ binding motif of GPR17 and is required for the recycling of the receptor to the plasma membrane. Most importantly, knockdown of SNX27 significantly increases GPR17 degradation and accelerates oligodendrocyte differentiation. Interestingly, we also found that in the brain of Ts65Dn mice (a model of Down syndrome) the trisomy-linked down-regulation of SNX27 expression correlates with a decrease in GPR17+ cells and an increase in mature oligodendrocytes. Our data highlight an important role for SNX27 in oligodendrocyte differentiation and myelination with possible consequences for pathology.