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Here, we demonstrate that genetic regulation of structural components of the axial skeleton, the intervertebral discs, and dense connective tissues (i.e., ligaments and tendons) is essential for the maintenance of spinal alignment. We show that the adhesion G protein-coupled receptor ADGRG6, previously implicated in human AIS association studies, is required in these tissues to maintain typical spine alignment in mice. Furthermore, we show that ADGRG6 regulates biomechanical properties of tendon and stimulates CREB signaling governing gene expression in cartilaginous tissues of the spine. Treatment with a cAMP agonist could mirror aspects of receptor function in culture, thus defining core pathways for regulating these axial cartilaginous and connective tissues. As\n                    <jats:italic>ADGRG6<\/jats:italic>\n                    is a key gene involved in human AIS, these findings open up novel therapeutic opportunities for human scoliosis.\n                  <\/jats:p>","DOI":"10.7554\/elife.67781","type":"journal-article","created":{"date-parts":[[2021,7,28]],"date-time":"2021-07-28T08:00:33Z","timestamp":1627459233000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.67781","source":"Crossref","is-referenced-by-count":35,"title":["An adhesion G protein-coupled receptor is required in cartilaginous and dense connective tissues to maintain spine alignment"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8032-1167","authenticated-orcid":true,"given":"Zhaoyang","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd, The University of Texas at Austin, Dell Medical School, Austin, United 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry","family":"Heckmann","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd, The University of Texas at Austin, Dell Medical School, Austin, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd, The University of Texas at Austin, Dell Medical School, Austin, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0387-4486","authenticated-orcid":true,"given":"Courtney M","family":"Karner","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jess G","family":"Snedeker","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich, Switzerland"},{"name":"Institute for Biomechanics, ETH Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9668-6497","authenticated-orcid":true,"given":"Ryan S","family":"Gray","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd, The University of Texas at Austin, Dell Medical School, Austin, United States"},{"name":"Department of Nutritional Sciences, The University of Texas at Austin, Austin, United 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