The adhesion G protein-coupled receptor GPR56 is a cell-autonomous regulator of oligodendrocyte development

Giera, Stefanie; Deng, Yiyu; Luo, Rong; Ackerman, Sarah D.; Mogha, Amit; Monk, Kelly R.; Ying, Yanqin; Jeong, Sung‐Jin; Makinodan, Manabu; Bialas, Allison R.; Chang, Bernard S.; Stevens, Beth; Corfas, Gabriel; Piao, Xiangshu

doi:10.1038/ncomms7121

Cited by 118 publications

(156 citation statements)

References 69 publications

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“…During this progression from OPC to oligodendrocyte, the Olig1-regulated G protein-coupled receptor (GPCR) Gpr17 is itself downregulated, resulting in the suppression of its nuclear effectors Id2 and Id4, otherwise potent inhibitors of oligodendroglial commitment (Chen et al, 2009). Another GPCR, Gpr56 (Adgrg1), is expressed and appears to be required for oligodendroglial lineage progression at this point Giera et al, 2015). As a result of this coordinated set of molecular events, OPCs commit to oligodendrocytic phenotype.…”

Section: Oligoneogenesis In the Forebrainmentioning

confidence: 99%

How to make an oligodendrocyte

2015

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Oligodendrocytes produce myelin, an insulating sheath required for the saltatory conduction of electrical impulses along axons. Oligodendrocyte loss results in demyelination, which leads to impaired neurological function in a broad array of diseases ranging from pediatric leukodystrophies and cerebral palsy, to multiple sclerosis and white matter stroke. Accordingly, replacing lost oligodendrocytes, whether by transplanting oligodendrocyte progenitor cells (OPCs) or by mobilizing endogenous progenitors, holds great promise as a therapeutic strategy for the diseases of central white matter. In this Primer, we describe the molecular events regulating oligodendrocyte development and how our understanding of this process has led to the establishment of methods for producing OPCs and oligodendrocytes from embryonic stem cells and induced pluripotent stem cells, as well as directly from somatic cells. In addition, we will discuss the safety of engrafted stem cell-derived OPCs, as well as approaches by which to modulate their differentiation and myelinogenesis in vivo following transplantation.

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Section: Oligoneogenesis In the Forebrainmentioning

confidence: 99%

How to make an oligodendrocyte

2015

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“…For example, the aGPCR GPR56/ADGRG1 is involved in cortex development, oligodendrocyte development, muscle cell development, innate immunity, and cancer progression (11)(12)(13)(14)(15)(16)(17). Recent studies have highlighted the role of GPR56 in promoting progression of acute myeloid leukemia (18) and progastrin-dependent colon cancer (19) and suggested that a GPR56 inhibitor would be clinically desirable.…”

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confidence: 99%

Stachel -independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

Salzman

Zhang

Gupta

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

101

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Adhesion G protein-coupled receptors (aGPCRs) play critical roles in diverse biological processes, including neurodevelopment and cancer progression. aGPCRs are characterized by large and diverse extracellular regions (ECRs) that are autoproteolytically cleaved from their membrane-embedded signaling domains. Although ECRs regulate receptor function, it is not clear whether ECRs play a direct regulatory role in G-protein signaling or simply serve as a protective cap for the activating "Stachel" sequence. Here, we present a mechanistic analysis of ECR-mediated regulation of GPR56/ADGRG1, an aGPCR with two domains [pentraxin and laminin/neurexin/sex hormonebinding globulin-like (PLL) and G protein-coupled receptor autoproteolysis-inducing (GAIN)] in its ECR. We generated a panel of high-affinity monobodies directed to each of these domains, from which we identified activators and inhibitors of GPR56-mediated signaling. Surprisingly, these synthetic ligands modulated signaling of a GPR56 mutant defective in autoproteolysis and hence, in Stachel peptide exposure. These results provide compelling support for a ligandinduced and ECR-mediated mechanism that regulates aGPCR signaling in a transient and reversible manner, which occurs in addition to the Stachel-mediated activation.adhesion GPCR | allostery | cell signaling | monobody | protein engineering

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“…That human patients with GPR56/ADGRG1 mutations present with white matter defects underscores the clinical importance of this adhesion GPCR in CNS myelination [68]. Gpr56-dependent OPC proliferation is mediated by Gα 12/13 -RhoA signaling [66,67], although the activating ligand for Gpr56/Adgrg1 in OPCs is currently unknown. In other cellular contexts, Gpr56/Adgrg1 can bind the ECM proteins tissue transglutaminase (TG2) and collagen III [69,70], and in the future it will be interesting to determine if either of these molecules activates Gpr56/Adgrg1 in OPCs.…”

Section: Adhesion Gpcrs In Oligodendrocyte Developmentmentioning

confidence: 99%

“…In the CNS, Gpr17 has been explored as a potential therapeutic target in remyelination either by inhibiting Gpr17 via antagonists or by activating the reserve pool of Gpr17-expressing OPCs to maturation [79,80]. As Gpr17 is enriched in white matter plaques of MS patients and in rodent models of MS, antagonism of Gpr17 or other inhibitory GPCRs may indeed be efficacious in future treatment strategies [57,64,66,67]. Additional GPCRs have been implicated in CNS myelin repair including Cxcr4, Gpr30, endothelin receptors, and sphingosine 1-phosphate receptors [81][82][83][84][85], underscoring the importance of this receptor super-family in myelin health and disease.…”

Section: Pharmacological Implications Of Gpcrs In Myelin Diseasesmentioning

confidence: 99%

“…Gpr56/Adgrg1 belongs to the same adhesion GPCR subfamily as Gpr126/Adgrg6 [10]. In the CNS, Gpr56/Adgrg1 is expressed in several cell types including OPCs, where this adhesion GPCR functions cell autonomously as an evolutionarily conserved regulator of OPC proliferation and differentiation [66,67]. In zebrafish and mouse Gpr56/Adgrg1 loss-of-function mutants, OPCs precociously differentiate before the full cohort of these cells are established such that hypomyelination is observed in later development.…”

Section: Adhesion Gpcrs In Oligodendrocyte Developmentmentioning

confidence: 99%

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G Protein-Coupled Receptors in Myelinating Glia

Mogha¹,

D’Rozario²,

Monk

2017

Trends in Pharmacological Sciences

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The G protein-coupled receptor (GPCR) super-family represents the largest class of functionally selective drug targets for disease modulation and therapy. GPCRs have been studied in great detail in central nervous system (CNS) neurons, yet these important molecules have been relatively understudied in glia. In recent years, however, exciting new roles for GPCRs in glial cell biology have emerged. Here, we focus on key roles for GPCRs in a specialized subset of glia, myelinating glia. We highlight recent work firmly establishing GPCRs as regulators of myelinating glial cell development and myelin repair. These advancements expand our understanding of myelinating glial cell biology and underscore the utility of targeting GPCRs to promote myelin repair in human disease. KeywordsG protein-coupled receptor (GPCR); myelination; Schwann cell; oligodendrocyte; remyelination An overview of G protein-coupled receptors in the nervous systemThe G protein-coupled receptor (GPCR) super-family of seven transmembrane (7TM) receptors comprises the largest class of cell membrane receptors [1]. GPCRs are activated by myriad stimuli including peptides, hormones, light, proteolytic processing of their Ntermini, small molecules, and more traditional protein ligands [2,3]. GPCRs have emerged as major pharmacological drug targets due to their key roles in a variety of physiological functions in disease and health, and GPCR modulators represent at least one-third of all clinically marketed drugs [4]. GPCRs can be classified into five families using the phylogenetically based GRAFS system: glutamate, rhodopsin, adhesion, frizzled, and secretin [5]. Glutamate is a major excitatory neurotransmitter in the nervous system, and * Correspondence: monkk@wustl.edu (K.R. Monk). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of interest statementThe authors declare no competing conflicts. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript accordingly, glutamate receptors have been studied in great detail with regard to their key roles in synaptic transmission, synapse formation, axon guidance, and development of neuronal circuits [6,7]. The rhodopsin family has by far the greatest number of GPCRs, and members are involved in photoreception and neurotransmission [5]. Frizzled GPCRs are activated by wingless/int (Wnt) proteins and control numerous cellular processes including neural crest development, patterning and adult neurogenesis [8]. Secretin receptors are classic hormone receptors, some of which have neuroprotective functions in the central nervou...

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The adhesion G protein-coupled receptor GPR56 is a cell-autonomous regulator of oligodendrocyte development

Cited by 118 publications

References 69 publications

How to make an oligodendrocyte

How to make an oligodendrocyte

Stachel -independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

G Protein-Coupled Receptors in Myelinating Glia

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