ADGRG6

Signaling

Upon lipopolysaccharide (LPS) or thrombin stimulation, expression of GPR126 is induced by MAP kinases in endothelial cells. During angiogenesis, GPR126 promotes protein kinase A (PKA)–cAMP-activated signaling in endothelial cells. Forced GPR126 expression in COS-7 cells enhances cAMP levels by coupling to heterotrimeric Gα_s/i proteins.

Function

GPR126 has been identified in genomic regions associated with adult height, more specially trunk height, pulmonary function and adolescent idiopathic scoliosis. In the vertebrate nervous system, many axons are surrounded by a myelin sheath to conduct action potentials rapidly and efficiently. Applying a genetic screen in zebrafish mutants, Talbot’s group demonstrated that GPR126 affects the development of myelinated axons. GPR126 drives the differentiation of Schwann cells through inducing cAMP levels, which causes Oct6 transcriptional activities to promote myelin gene activity. Mutation of gpr126 in zebrafish affects peripheral myelination. Monk’s group demonstrated domain-specific functions of GPR126 during Schwann cells development: the NTF is necessary and sufficient for axon sorting, while the CTF promotes wrapping through cAMP induction to regulate early and late stages of Schwann cells development.

Outside of neurons, GPR126 function is required for heart and inner ear development. GPR126 stimulates VEGF signaling and angiogenesis by modulating VEGF receptor 2 (VEGFR2) expression through STAT5 and GATA2 in endothelial cells.

Disease

Mouse models have shown GPR126 deletion to affect cartilage biology and spinal column development, supporting findings that variants of GPR126 have been associated with adolescent idiopathic scoliosis, and Mutations have been shown to be responsible for severe arthrogryposis multiplex congenita