The Orphan Adhesion-GPCR GPR126 Is Required for Embryonic Development in the Mouse

Waller-Evans, Helen; Prömel, Simone; Langenhan, Tobias; Dixon, John; Zahn, Dirk; Colledge, William H; Doran, Joanne; Carlton, Mark; Davies, Benjamin; Aparicio, Samuel; Grosse, Johannes; Russ, Andreas

doi:10.1371/journal.pone.0014047

Cited by 81 publications

(98 citation statements)

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“…These results are concordant with a report that demonstrated that Gpr126 is expressed in endothelial cells, and the expression could be induced by angiogenic factors (29). Severe cardiovascular defects that result in embryonic lethality were observed in the Gpr126 knock-out mouse (28). Waller-Evans et al (28) did find internal hemorrhaging in mutant embryos, although no obvious vasculogenesis defect was identified.…”

Section: Discussionsupporting

confidence: 91%

“…GPR126 is a seven-transmembrane receptor that is evolutionarily conserved not only in the protein sequence but also in synteny of the surrounding genomic region in vertebrates (28). Besides the conserved protein sequences, recent studies have reported that GPR126 has conserved physiological functions during peripheral nerve development in fish and mammals (26,27).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Gpr126 was identified to be essential for Schwann cells to initiate myelination through induction of key transcriptional factors both in zebrafish and mice, suggesting its evolutionarily conserved functions (26,27). Deletion of Gpr126 in mice leads to midgestation embryonic lethality due to internal hemorrhaging and failures in cardiovascular development (28). Although GPR126 is present in human umbilical vein endothelial cells and its expression is increased after the cells are challenged by lipopolysaccharide and thrombin (29), the precise roles of GPR126 in angiogenesis were not investigated.…”

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confidence: 99%

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GPR126 Protein Regulates Developmental and Pathological Angiogenesis through Modulation of VEGFR2 Receptor Signaling

Cui

Wang

Huang

et al. 2014

Journal of Biological Chemistry

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Background: GPR126 plays critical roles in development, but its function in vessels is not well characterized. Results: GPR126 regulates angiogenesis by modulating endothelial cell proliferation and migration via regulation of Vegfr2 expression. Conclusion: GPR126 is important for physiological and pathological angiogenesis. Significance: This finding provides a new functional mechanism for the regulation of angiogenesis.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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GPR126 Protein Regulates Developmental and Pathological Angiogenesis through Modulation of VEGFR2 Receptor Signaling

Cui

Wang

Huang

et al. 2014

Journal of Biological Chemistry

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“…This initiative has revealed that Gpr126, a vertebrate aGPCR essential for the myelination of peripheral nerves by Schwann cells (Monk et al, 2009(Monk et al, , 2011, is required for embryonic viability and cardiovascular development in the mouse (Waller-Evans et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Characterization and functional study of a cluster of four highly conserved orphan adhesion‐GPCR in mouse

Prömel

Waller-Evans

Dixon

et al. 2012

Developmental Dynamics

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Background: Adhesion G protein-coupled receptors (aGPCR) constitute a structurally and functionally diverse class of seven-transmembrane receptor proteins. Although for some of the members important roles in immunology, neurology, as well as developmental biology have been suggested, most receptors have been poorly characterized. Results: We have studied evolution, expression, and function of an entire receptor group containing four uncharacterized aGPCR: Gpr110, Gpr111, Gpr115, and Gpr116. We show that the genomic loci of these four receptors are clustered tightly together in mouse and human genomes and that this cluster likely derives from a single common ancestor gene. Using transcriptional profiling on wild-type and knockout/LacZ reporter knockin mice strains, we have obtained detailed expression maps that show ubiquitous expression of Gpr116, co-expression of Gpr111 and Gpr115 in developing skin, and expression of Gpr110 in adult kidney. Loss of Gpr110, Gpr111, or Gpr115 function did not result in detectable defects, indicating that genes of this aGPCR group might function redundantly. Conclusions: The aGPCR cluster Gpr110, Gpr111, Gpr115, and Gpr116 developed from one common ancestor in vertebrates. Expression suggests a role in epithelia, and one can speculate about a possible redundant function of GPR111 and GPR115. Developmental Dynamics 241:1591-1602, 2012.V C 2012 Wiley Periodicals, Inc.

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“…Adhesion GPCR are characterized by long extracellular N termini, which are composed of multiple functional domains, a seven-transmembrane spanning (7TM) domain, and a cytoplasmic tail. Adhesion GPCR are believed to play a role in immune functions (3,4), angiogenesis (5), cell polarity (6,7), and development (8,9). Mutations in some members of the protein family were identified as the cause of inherited developmental defects in humans such as Usher syndrome (VLGR1) (10) and bilateral frontoparietal polymicrogyria (GPR56) (11).…”

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confidence: 99%

Cell Adhesion Receptor GPR133 Couples to Gs Protein

Bohnekamp

Schöneberg

2011

Journal of Biological Chemistry

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Adhesion G protein-coupled receptors (GPCR), with their very large and complex N termini, are thought to participate in cell-cell and cell-matrix interactions and appear to be highly relevant in several developmental processes. Their intracellular signaling is still poorly understood. Here we demonstrate that GPR133, a member of the adhesion GPCR subfamily, activates the G s protein/adenylyl cyclase pathway. The presence of the N terminus and the cleavage at the GPCR proteolysis site are not required for G protein signaling. G s protein coupling was verified by G␣ s knockdown with siRNA, overexpression of G␣ s , coexpression of the chimeric Gq s4 protein that routes GPR133 activity to the phospholipase C/inositol phosphate pathway, and missense mutation within the transmembrane domain that abolished receptor activity without changing cell surface expression. It is likely that not only GPR133 but also other adhesion GPCR signal via classical receptor/G protein-interaction.Adhesion receptors comprise the second largest subfamily of putatively G protein-coupled receptors (GPCR) 2 with more than 30 members in vertebrates (1, 2). Adhesion GPCR are characterized by long extracellular N termini, which are composed of multiple functional domains, a seven-transmembrane spanning (7TM) domain, and a cytoplasmic tail. Adhesion GPCR are believed to play a role in immune functions (3, 4), angiogenesis (5), cell polarity (6, 7), and development (8, 9). Mutations in some members of the protein family were identified as the cause of inherited developmental defects in humans such as Usher syndrome (VLGR1) (10) and bilateral frontoparietal polymicrogyria (GPR56) (11). Although there is consensus on the fact that this receptor class mediates essential cellcell and cell-matrix interactions (1, 12), the molecular mechanism of intracellular signal transduction of adhesion GPCR remains obscure.There are only a few studies on intracellular signaling mechanisms of adhesion GPCR. Latrophilin 1, the prototype of adhesion GPCR, induces intracellular Ca 2ϩ signaling upon interaction with the exogenous ligand ␣-latrotoxin (13, 14). GPR56 appears to activate the G 12/13 protein/Rho pathway after stimulation with an antibody against the ectodomain (15). BAI1 recognizes phosphatidylserine and can directly recruit a Racguanine nucleotide exchange factor (Rac-GEF) complex to mediate the uptake of apoptotic cells (16). The cytoplasmic domain of BAI2 interacts with GA-binding protein ␥, and GAbinding protein-␣/␥ or GA-binding protein-␣/␤ work as transcriptional repressors of VEGF (17). However, clear evidence of intracellular signaling for most adhesion GPCR via G proteins is still missing (12).Genetic variations in the GPR133 gene, also a member of the adhesion GPCR family, were associated with adult height (18) and the RR interval duration in electrocardiograms (19). GPR133 is expressed in CNS (20) and other tissues; its endogenous agonists and the signal transduction are unknown. Here we demonstrate that GPR133 is coupled to the G s protein/adeny...

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The Orphan Adhesion-GPCR GPR126 Is Required for Embryonic Development in the Mouse

Cited by 81 publications

References 33 publications

GPR126 Protein Regulates Developmental and Pathological Angiogenesis through Modulation of VEGFR2 Receptor Signaling

GPR126 Protein Regulates Developmental and Pathological Angiogenesis through Modulation of VEGFR2 Receptor Signaling

Characterization and functional study of a cluster of four highly conserved orphan adhesion‐GPCR in mouse

Cell Adhesion Receptor GPR133 Couples to Gs Protein

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