Abstract
Craniosynostosis is a major craniofacial congenital disorder that causes developmental complications. During normal cranial development, intramembranous ossification forms the flat bones and sutures, while cartilage appears transiently in the posterior calvarial region. However, in craniosynostosis, premature suture fusion disturbs normal calvarial morphogenesis. To clarify the role of transient cartilage in this morphogenetic disruption, we investigated its molecular regulation and pathology in mice, focusing on parathyroid hormone 1 receptor (Pth1r) signaling. Conditional deletion of Pth1r in the cranial mesenchyme unexpectedly caused acrocephalic dysmorphology and craniosynostosis, with altered cartilage differentiation. Occipito–interparietal synostosis consistently occurred in Pth1r-ablated Gli1+ and Acan+ lineages, but not after adult Gli1-CreERT2 deletion, indicating a developmental role. Bulk and single-cell RNA-seq analysis revealed nine mesenchymal subsets, with mutant cells showing abnormal chondrocyte differentiation and upregulated Indian hedgehog (Ihh) signaling. These findings indicate that Pth1r maintains proper chondrogenic regulation during calvarial development, and its loss induces craniosynostosis through Ihh overactivation.
Similar content being viewed by others
Acknowledgements
We thank Drs. Beate Lanske (Radius Health, Boston, MA, USA) and Tatsuya Kobayashi (Massachusetts General Hospital, Boston, MA, USA) for sharing mouse resources. We appreciate KN International Inc. (Tokyo, Japan) and the assistance of Michael Densmore (Essential Scientific Editing, Boston, MA, USA) for English editing. Yuji Fujimoto is deceased. This work is supported by JSPS KAKENHI (16K20572, 23K09331), Takeda science foundation, The Ichiro Kanehara foundation for the promotion of medical sciences and medical care (19KI21) and the Nakatomi Foundation (to K.A.).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Source data
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Amano, K., Okuzaki, D., Fujimoto, Y. et al. The role of Pth1r in posterior cranium cartilage regulation and craniosynostosis. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71797-y
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41467-026-71797-y
