Oligodendrogenesis: focus on G protein-coupled receptor 17 (GPR17)

It is now well known that not only neurons, but also glial cells play a crucial role in the regeneration of nervous tissue. Oligodendrocytes are responsible for synthesising myelin, and studying their development and maturation is an important means of finding new approaches to the treatment of demyelinating diseases. During adult life, oligodendrocyte precursor cells (OPCs) scattered throughout the brain parenchyma continue to differentiate into mature oligodendrocytes that wrap neuronal axons with myelin in specific brain areas, However, this process is abolished by demyelinating diseases such as multiple sclerosis, whose evolution blocks the maturation of OPCs during an early stage of development and therefore leads to a lack of mature oligodendrocytes. It has recently emerged that GPR17 is an intrinsic timer that regulates the transition of OPCs to pre-myelinating oligodendrocytes: it is required for the initial differentiation of OPCs but then has to be down-regulated in order to allow final myelination. Consequently, alterations in GPR17 expression lead to defective myelination. On the basis of these findings, we investigated the post-transcriptional and post-translational mechanisms involved in GPR17 expression. It was already known that transcription factors ID2/ID4 indirectly regulate the expression of GPR17 by sequestering the Olig1/2 inhibitors of GPR17 expression, and our findings demonstrate that blocking the pathways involved in the up-regulation of ID2/ID4, such as the Wnt pathway, rapidly down-regulates GPR17, thus allowing cells to enter the later phases of maturation as shown by the presence of myelin protein MBP. On the contrary, blocking the pathways involved in the down-regulation of ID2/ID4, such as the mTOR pathway, up-regulates GPR17, which is stably expressed on the plasma membrane and prevents full cell maturation. GPR17 can also be modulated post-translationally by means of intracellular trafficking: like many receptors, it is internalised in endosomes and then sorted into lysosomes or recycled to the plasma membrane, and the balance of these two processes (degradation or recycling) modulates its expression and may affect OPC differentiation. We therefore analysed the effects on GPR17 of sorting nexin 27 (SNX27), a PDZ motif protein known to be required for the recycling of a number of receptors via interactions with their PDZ-binding domains, and found that: i) the C-terminal PDZ-binding motif of GPR17 specifically interacts with SNX27; ii) mutations in the PDZ-binding motif of GPR17 alter receptor recycling; iii) the knockdown of SNX27 expression significantly accelerates GPR17 degradation; and iv), the down-regulation of GPR17 correlates with increases in the expression of myelin proteins MAG and MBP, and OPC differentiation. In conclusion, our findings indicate that the Wnt and mTOR pathways may differently regulate GPR17 expression, and that the modulation of receptor trafficking to the plasma membrane may play an important role in oligodendrocyte differentiation. Controlling these pathways may therefore be an appropriate target in the development of new treatments for demyelinating diseases.