A G protein-coupled receptor is required in cartilaginous and dense connective tissues to maintain spine alignment
- University of Texas at Austin, United States
- University of Zurich, Switzerland
- Central South University, China
- University of Texas at Austin - Dell Pediatrics Research Institute, United States
- University of Texas Southwestern Medical Center, United States
- ETH Zurich, Switzerland
Abstract
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 (i.e., ligaments and tendons) are 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 ADGRG6 is a key gene involved in human AIS, these findings open up novel therapeutic opportunities for human scoliosis.
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All data generated or analyzed during this study are included in the manuscript and supporting files.
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Funding
NIH Office of the Director (R01AR072009)
- Ryan S Gray
NIH Office of the Director (R01AR071967)
- Courtney M Karner
NIH Office of the Director (R01AR076325)
- Courtney M Karner
NIH Office of the Director (F32AR073648)
- Zhaoyang Liu
Vontobel-Stiftung
- Jess G Snedeker
NIH Office of the Director (K99AR077090)
- Zhaoyang Liu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (AUP-2018-00276) of the University of Texas at Austin.
Copyright
© 2021, Liu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A G protein-coupled receptor is required in cartilaginous and dense connective tissues to maintain spine alignment
eLife 10:e67781.
https://doi.org/10.7554/eLife.67781
