Structure, ligands, and roles of GPR126/ADGRG6 in the development and diseases

Li, Qi; Huo, Anran; Li, Mengqi; Wang, Jiali; Yin, Qiang; Chen, Lumiao; Chu, Xin; Qin, Yuan; Qi, Yuwan; Li, Yang; Cui, Heping; Cong, Qifei

doi:10.1016/j.gendis.2023.02.016

Cited by 6 publications

(3 citation statements)

References 82 publications

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“…Brain ECs are embedded in the BM with pericytes, and both cell types contribute to the secretion of components like collagen IV and fibronectin, laminin-211 (α2β1γ1), laminin-511 (α5β1γ1), and laminin-411 (α4β1γ1) ( 57 ). As an adhesion GPCR, GPR126 has an important role during development via many processes, primarily through cell-cell and cell-ECM interactions, by binding to collagen IV or laminin-211 ( 28 , 29 , 34 ). Thus, we analyzed the structure and composition of the vascular BM.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, GPR126 plays crucial roles in various organ and tissue development, including Schwann cells and peripheral nervous system myelination, bone formation, inner ear development, and placental development ( 32 – 34 ). Human GPR126 mutations are associated with non-neurological diseases like adolescent idiopathic scoliosis ( 35 ), arthrogryposis multiplex congenita ( 36 ), and carcinogenesis ( 31 ).…”

Section: Introductionmentioning

confidence: 99%

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GPR126 is a specifier of blood-brain barrier formation in the mouse central nervous system

Kakogiannos,

Scalise,

Martini

et al. 2024

Journal of Clinical Investigation

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The blood-brain barrier (BBB) acquires unique properties to regulate neuronal function during development. The formation of the BBB, which occurs in tandem with angiogenesis, is directed by the Wnt/β-catenin signaling pathway. Yet the exact molecular interplay remains elusive. Our study reveals the G protein–coupled receptor GPR126 as a critical target of canonical Wnt signaling, essential for the development of the BBB’s distinctive vascular characteristics and its functional integrity. Endothelial cell–specific deletion of the Gpr126 gene in mice induced aberrant vascular morphogenesis, resulting in disrupted BBB organization. Simultaneously, heightened transcytosis in vitro compromised barrier integrity, resulting in enhanced vascular permeability. Mechanistically, GPR126 enhanced endothelial cell migration, pivotal for angiogenesis, acting through an interaction between LRP1 and β 1 integrin, thereby balancing the levels of β 1 integrin activation and recycling. Overall, we identified GPR126 as a specifier of an organotypic vascular structure, which sustained angiogenesis and guaranteed the acquisition of the BBB properties during development.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

GPR126 is a specifier of blood-brain barrier formation in the mouse central nervous system

Kakogiannos,

Scalise,

Martini

et al. 2024

Journal of Clinical Investigation

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“…Besides having a possible role in inflammation, tissue repair mechanisms triggered by Gpr126 signaling are also imaginable. For example, Gpr126 is critical for the repair process of peripheral nerve damage by ensuring Schwann cell function [13,60]. While a lot of effort has been made to study the pathophysiology of the PT, the glomerulus, and the vasculature in AKI [61], only little is known about the role of the CD in this condition.…”

Section: Discussionmentioning

confidence: 99%

Adhesion G Protein-Coupled Receptor Gpr126 (Adgrg6) Expression Profiling in Diseased Mouse, Rat, and Human Kidneys

Kösters,

Cazorla-Vázquez,

Krüger

et al. 2024

Cells

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Uncovering the function of understudied G protein-coupled receptors (GPCRs) provides a wealth of untapped therapeutic potential. The poorly understood adhesion GPCR Gpr126 (Adgrg6) is widely expressed in developing kidneys. In adulthood, Gpr126 expression is enriched in parietal epithelial cells (PECs) and epithelial cells of the collecting duct and urothelium. Whether Gpr126 plays a role in kidney disease remains unclear. Here, we characterized Gpr126 expression in diseased kidneys in mice, rats, and humans. RT-PCR data show that Gpr126 expression is altered in kidney disease. A quantitative RNAscope® analysis utilizing cell type-specific markers revealed that Gpr126 expression upon tubular damage is mainly increased in cell types expressing Gpr126 under healthy conditions as well as in cells of the distal and proximal tubules. Upon glomerular damage, an increase was mainly detected in PECs. Notably, Gpr126 expression was upregulated in an ischemia/reperfusion model within hours, while upregulation in a glomerular damage model was only detected after weeks. An analysis of kidney microarray data from patients with lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis (FSGS), hypertension, and diabetes as well as single-cell RNA-seq data from kidneys of patients with acute kidney injury and chronic kidney disease indicates that GPR126 expression is also altered in human kidney disease. In patients with FSGS, an RNAscope® analysis showed that GPR126 mRNA is upregulated in PECs belonging to FSGS lesions and proximal tubules. Collectively, we provide detailed insights into Gpr126 expression in kidney disease, indicating that GPR126 is a potential therapeutic target.

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