Mice lacking Gpr37 exhibit decreased expression of the myelin-associated glycoprotein MAG and increased susceptibility to demyelination

Abstract

GPR37 is an orphan G protein-coupled receptor that is predominantly expressed in the brain and found at particularly high levels in oligodendrocytes. GPR37 has been shown to exert effects on oligodendrocyte differentiation and myelination during development, but the molecular basis of these actions is incompletely understood and moreover nothing is known about the potential role(s) of this receptor under demyelinating conditions. To shed light on the fundamental biology of GPR37, we performed proteomic studies comparing protein expression levels in the brains of mice lacking GPR37 and its close relative GPR37-like 1 (GPR37L1). These studies revealed that one of the proteins most sharply decreased in the brains of Gpr37/Gpr37L1 double knockout mice is the myelin-associated glycoprotein MAG. Follow-up Western blot studies confirmed this finding and demonstrated that genetic deletion of Gpr37, but not Gpr37L1, results in strikingly decreased brain expression of MAG. Further in vitro studies demonstrated that GPR37 and MAG form a complex when expressed together in cells. As loss of MAG has previously been shown to result in increased susceptibility to brain insults, we additionally assessed Gpr37-knockout (Gpr37−/−) vs. wild-type mice in the cuprizone model of demyelination. These studies revealed that Gpr37−/− mice exhibit dramatically increased loss of myelin in response to cuprizone, yet do not show any increased loss of oligodendrocyte precursor cells or mature oligodendrocytes. These findings reveal that loss of GPR37 alters oligodendrocyte physiology and increases susceptibility to demyelination, indicating that GPR37 could be a potential drug target for the treatment of demyelinating diseases such as multiple sclerosis.

Protective effects of GPR37 via regulation of inflammation and multiple cell death pathways after ischemic stroke in mice

“…On the other hand, in vitro studies suggest that endogenously expressed GPR37 plays a cytoprotective role following cellular insults (17,18). Moreover, deletion of GPR37 was found to result in greater demyelination in vivo following treatment of mice with cuprizone (54). The data shown in the present study are consistent with the idea that GPR37 plays a predominantly protective role against ischemic insults in vivo.…”

Shared loci of telomere length with brain morphology, and pleiotropy in transcriptomic and epigenomic profiles of brain

“…The brain transcriptomic integrated association studies highlighted genes that are involved with both LTL and neuronal effects. GPR37 (G-protein coupled receptor 37) is expressed in oligodendrocytes in different tissues of the brain contributing to myelination regulation (Smith et al, 2017). GPR37 is associated with telomere length and serves as stress response neuroprotective gene.…”

Human glial progenitor cells effectively remyelinate the demyelinated adult brain

“…In contrast, the Notch pathway inhibitor of differentiation JAG1 was sharply repressed (John et al, 2002), suggesting the incipient differentiation of these cells. Also localizing to this module and upregulated in remyelinating GPCs was GPR37, the expression of which attends and is necessary for oligodendrocyte differentiation (Smith et al, 2017;Yang et al, 2016). Interestingly, CIP2A, a transcriptional repressor of GPR37, was profoundly down-regulated in cuprizone-mobilized hGPCs, again suggesting that cuprizone-demyelination triggers the active disinhibition of oligodendrocytic differentiation by previously quiescent parenchymal hGPCs (Yang et al, 2016).…”