Gpr126 (Adgrg6) is expressed in cell types known to be exposed to mechanical stimuli

Abstract

GPR126 (ADGRG6) is an adhesion G protein–coupled receptor that plays an important role in a variety of tissues/organs, such as heart, sciatic nerve, cartilage, and ear. Moreover, GPR126 (ADGRG6) mutations are associated with human diseases, like adolescent idiopathic scoliosis, lung disease, bladder cancer, and intellectual disability. Despite its clinical importance, it remains elusive how GPR126 is activated and mediates signal transduction and what cellular processes depend on GPR126 signaling. Here, we generated a lacZ reporter mouse line to determine endogenous Gpr126 (Adgrg6) expression in a cell type‐specific manner during embryonic development, at postnatal day 5 and in adult animals. Our results confirm Gpr126 expression data previously obtained utilizing antibodies and in situ hybridization in embryonic heart and sciatic nerve. In addition, we provide data with cellular resolution for previously described RT‐PCR–based data, including lung and bladder. Moreover, new Gpr126‐expressing tissues and cell types were identified, such as ureter and acinar secretory cells. Collectively, our data demonstrate that the newly generated lacZ reporter mouse is a suitable model to study Gpr126 expression during development and adulthood, provide detailed insight into Gpr126 expression at the cellular level, and reveal that all identified Gpr126‐expressing cells are known to be exposed to mechanical stimuli.

Transcriptomic analysis of pulmonary artery smooth muscle cells identifies new potential therapeutic targets for idiopathic pulmonary arterial hypertension

“…We found small changes in cAMP in the gain‐ and loss‐of‐function experiments and that treatment with the putative ADGRG6 agonist Collagen IV (Paavola et al, 2014) did not change cellular cAMP levels. However, activation of this GPCR may require mechanical activation, as it is expressed in cell types that undergo mechanical stress (Musa et al, 2019) and activated mechanically by laminin‐211 (Petersen et al, 2015). Further work examining the relationship of ADGRG6 and other factors involved in cAMP signalling and proliferation in PASMCs, and perhaps other smooth muscle cells, is needed.…”

Soluble dimeric prion protein ligand activates Adgrg6 receptor but does not rescue early signs of demyelination in PrP-deficient mice

“…While comparison of the transcriptional changes in different tissues as was presented here must be interpreted with great caution, the possibility of myotoxicity induced by a PrP-based agent should not be discounted. Early studies suggested that Adgrg6 is expressed in muscle tissue [45], but a recent study objected that Adgrg6 detected in muscle homogenate derived from endothelial cells instead of muscle cells [46]. Thus, it remains unclear whether the toxic effect of PrP is mediated by Adgrg6 or by other interaction partners.…”

miR‐27a/b is a posttranscriptional regulator of Gpr126 (Adgrg6)

“…S1C, online only). In addition, miR‐27a and miR‐27b have previously been associated with physiology and pathophysiology of tissues and organs in which Gpr126 is expressed, including heart, bladder, vasculature, and salivary gland . Moreover, miR‐27a, miR‐27b, and Gpr126 are shear stress–regulated in HUVEC cells …”

“…miR‐27b and Gpr126 are both expressed during heart development and in endothelial cells, are both shear stress–regulated, and associated with cognitive impairment or intellectual disability, as well as bladder cancer . In addition, it is known that Gpr126 is expressed in the salivary gland, lung, and kidney, while miR‐27b is associated with non‐small cell lung cancer, clear cell renal cell cancer, and adenoid cystic carcinoma of the salivary glands . Moreover, miR‐27b has been shown to regulate the expression of delta‐like ligand 4 ( Dll4 ), which activates Notch signaling, an established regulatory pathway of Gpr126 expression in HUVECs and the endocardium of the developing heart …”

“…Recently, it has been established that Gpr126 is expressed in a variety of tissues/organs that are subject to mechanical stimuli, such as heart, lung, bladder, kidney, cartilage, vasculature, and salivary gland . In addition, GPR126 mutations are associated with human diseases, such as intellectual disability, bladder cancer, adolescent idiopathic scoliosis, arthrogryposis multiplex congenital, syndromes with auricular phenotypes, lung disease, and neuromuscular disease .…”