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Gnas Loss Causes Chondrocyte Fate Conversion in Cranial Suture Formation.
- Source :
- Journal of Dental Research; Jul2022, Vol. 101 Issue 8, p931-941, 11p, 1 Color Photograph, 2 Charts, 2 Graphs
- Publication Year :
- 2022
-
Abstract
- Calvaria development is distinct from limb formation. Craniosynostosis is a skull deformity characterized by premature cranial suture fusion due to the loss of the GNAS gene and, consequently, its encoded protein Gα<subscript>s</subscript>. This birth defect requires surgery, with potential lethal consequences. So far, hardly any early-stage nonsurgical interventions for GNAS loss-related craniosynostosis are available. Here, we investigated the role of the Gnas gene in mice in guarding the distinctiveness of intramembranous ossification and how loss of Gnas triggered endochondral-like ossification within the cranial sutures. Single-cell RNA sequencing (scRNA-seq) of normal neonatal mice cranial suture chondrocytes showed a Hedgehog (Hh) inactivation pattern, which was associated with Gα<subscript>s</subscript> signaling activation. Loss of Gnas evoked chondrocyte-to-osteoblast fate conversion and resulted in cartilage heterotopic ossification (HO) within cranial sutures and fontanels of the mouse model, leading to a skull deformity resembling craniosynostosis in patients with loss of GNAS. Activation of ectopic Hh signaling within cranial chondrocytes stimulated the conversion of cell identity through a hypertrophy-like stage, which shared features of endochondral ossification in vivo. Reduction of Gli transcription activity by crossing with a loss-of-function Gli2 allele or injecting GLI1/2 antagonist hindered the progression of cartilage HO in neonatal stage mice. Our study uncovered the role of Gα<subscript>s</subscript> in maintaining cranial chondrocyte identity during neonatal calvaria development in mice and how reduction of Hh signaling could be a nonsurgical intervention to reduce skull deformity in craniosynostosis due to loss of GNAS. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00220345
- Volume :
- 101
- Issue :
- 8
- Database :
- Complementary Index
- Journal :
- Journal of Dental Research
- Publication Type :
- Academic Journal
- Accession number :
- 157868298
- Full Text :
- https://doi.org/10.1177/00220345221075215