GPR37 Modulates Remyelination Following Demyelinating Injury

Abstract

GPR37 has been recognized as a negative regulator of oligodendrocyte myelination. However, its role in demyelination recovery remains unclear. To examine the function of GPR37 in remyelination, we compared wild-type and GPR37-deficient mice of either sex after focal (lysolecithin) or global (cuprizone) toxin-induced demyelination, as well as immune-mediated demyelination (experimental autoimmune encephalomyelitis, EAE). We found that the absence of GPR37 resulted in enhanced recovery in all three models. In focal demyelination, we observed that, while the initial lesioned area was similar in size between genotypes, 2 weeks after induction of demyelination, the remyelinated area was markedly larger and lesion size was reduced in Gpr37 null mice compared with wild-type animals. Unlike local demyelination, which induced similar demyelination in both genotypes, cuprizone induced much faster and more severe demyelination in the mutant's corpus callosum. However, we observed a significant increase in remyelination in the mutant mice compared with their wild-type counterparts. After immune-mediated demyelination, the clinical scores of Gpr37 null mice were lower than those of wild-type animals from Day 16 postinduction of EAE. Similar results were obtained in mice lacking GPR37 specifically in oligodendrocytes, indicating that faster recovery after EAE is cell autonomous. Our study suggests that GPR37 is both myelin-protective and negatively regulates remyelination in the adult brain. Furthermore, our findings demonstrate that GPR37 exhibits context-dependent functions across distinct demyelinating disease models.