G-Protein-Coupled Receptor Gpr17 Expression in Two Multiple Sclerosis Remyelination Models

Abstract

In multiple sclerosis patients, demyelination is prominent in both the white and gray matter. Chronic clinical deficits are known to result from acute or chronic injury to the myelin sheath and inadequate remyelination. The underlying molecular mechanisms of remyelination and its failure remain currently unclear. Recent studies have recognized G protein-coupled receptor 17 (GPR17) as an important regulator of oligodendrocyte development and remyelination. So far, the relevance of GPR17 for myelin repair was mainly tested in remyelinating white matter lesions. The relevance of GPR17 for gray matter remyelination as well as remyelination of chronic white matter lesions was not addressed so far. Here, we provide a detailed characterization of GPR17 expression during experimental de- and remyelination. Experimental lesions with robust and limited endogenous remyelination capacity were established by either acute or chronic cuprizone-induced demyelination. Furthermore, remyelinating lesions were induced by the focal injection of lysophosphatidylcholine (LPC) into the corpus callosum. GPR17 expression was analyzed by complementary techniques including immunohistochemistry, in situ hybridization, and real-time PCR. In control animals, GPR17 cells were evenly distributed in the corpus callosum and cortex and displayed a highly ramified morphology. Virtually all GPR17 cells also expressed the oligodendrocyte-specific transcription factor OLIG2. After acute cuprizone-induced demyelination, robust endogenous remyelination was evident in the white matter corpus callosum but not in the gray matter cortex. Endogenous callosal remyelination was paralleled by a robust induction of GPR17 expression which was absent in the gray matter cortex. Higher numbers of GPR17 cells were as well observed after LPC-induced focal white matter demyelination. In contrast, densities of GPR17 cells were comparable to control animals after chronic cuprizone-induced demyelination indicating quiescence of this cell population. Our findings demonstrate that GPR17 expression induction correlates with acute demyelination and sufficient endogenous remyelination. This strengthens the view that manipulation of this receptor might be a therapeutic opportunity to support endogenous remyelination.

Macroglial diversity: white and grey areas and relevance to remyelination

“…More specifically, the initiation and peak of complete demyelination is delayed in the cortex compared to the corpus callosum [19]. Several studies report that remyelination is more efficient in the corpus callosum than in the cortex upon cuprizone intoxication [202,203]. However, limitations of the cuprizone model are that after initial demyelination, myelin debris clearance parallels the early processes of remyelination, i.e., mature OLGs appear regardless of whether the cuprizone diet is maintained or not [204].…”

“…3). In the corpus callosum, GPR17 is expressed by maturing oligodendroglial lineage cells, where it is involved in the initiation of differentiation [202]. Timely downregulation of GPR17 is required for terminal OLG differentiation and myelination.…”

Metabolomic and transcriptomic signatures of prenatal excessive methionine support nature rather than nurture in schizophrenia pathogenesis

“…Several pieces of evidence support the disrupted myelination in MET mice: 1) alongside the increase in LPCs, the myelination gene Gpr17 was upregulated. GPR17 is a Gprotein coupled receptor that regulates oligodendrocyte differentiation in response to LPC-induced demyelination 30,36,37 , and is overexpressed in brain tissues experiencing demyelination injuries [38][39][40] ; 2) arachidonic acid derivatives (such as cysteinyl leukotrienes (LTC4 and LTD4), can directly regulate GPR17 [41][42][43] , and therefore the dysregulation of arachidonic acid pathways found in MET brains might be implicated in the demyelination; 3) the brains of newborn MET pups exhibited an increase in the mRNA and immunoreactivity of GFAP, a marker for neuroinflammation as well as myelination; [44][45][46][47] and 4) finally, the MET brains displayed an overexpression of Serpina3n, an astrocyte specific protein and neuro-inflammation marker. Strikingly, Serpin3a (the human analogue of Serpina3n) displays the highest fold-changes in the brains of schizophrenia patients (2-fold increase, P = 1.14E-13, FDR = 1.62E-10), and two-fold increase in autism (P = 0.004154, FDR = 0.059) 48 .…”

Aquaporin-4 Expression during Toxic and Autoimmune Demyelination

“…All in vivo experiments were performed as published previously with minor modifications [ 29 , 30 , 31 ]. Eight-week-old C57BL/6 female and male mice (19 g–20 g) were purchased from Janvier Labs, Le Genest-Saint-Isle, France.…”