A G protein-coupled receptor is required in cartilaginous and dense connective tissues to maintain spine alignment

Summary Adolescent idiopathic scoliosis (AIS) is the most common spine disorder affecting children worldwide, yet little is known about the pathogenesis of this disorder. Here, we demonstrate that genetic regulation of structural components of the axial skeleton, the intervertebral discs and dense connective tissues (e.g., ligaments and tendons), are essential for maintenance of spinal alignment. We show that the G-coupled protein receptor Adgrg6 , previously implicated in human AIS association studies, is required in these tissues to maintain typical spine morphology. We show that Adgrg6 regulates biomechanical properties of tendon and stimulates CREB signaling governing gene expression in cartilaginous tissues of the spine. Treatment with an cAMP agonist was able to mirror aspects of receptor function in culture defining core pathways for regulation of these axial connective tissues. As ADGRG6 is a key gene involved in human AIS, these findings open up novel therapeutic opportunities for human scoliosis. Highlights Knockout mice lacking Adgrg6 function in the tendons and ligaments of the spine develop perinatal-onset thoracic scoliosis. Loss of Adgrg6 function in cartilaginous tissues of the discs contribute to the incidence and severity of scoliosis. The loss of Adgrg6 function in spine tissues provide a model of construct validity for human adolescent idiopathic scoliosis Fine tuning of the biomechanical properties of dense connective tissues is essential for maintaining spine alignment.