C2CD3 links tooth patterning to evolutionary tooth loss in birds and dental anomalies across vertebrates
18 affiliations
- 1Division of Pediatric Dentistry, Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
- 2Division of Pediatric Dentistry, Center of Excellence in Medical Genetics Research, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
- 3Department of Pedodontics, Faculty of Dentistry, Istanbul University, Istanbul 34116, Türkiye
- 4Dental department, Rayong Hospital, Rayong 21000, Thailand
- 5Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229
- 6Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267
- 7Division of Plastic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229
- 8Centre for Craniofacial and Regenerative Biology, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, Guy’s Hospital, London SE1 9RT, United Kingdom
- 9Faculty of Dentistry, Burapha University, Saen Suk, Chon Buri 20131, Thailand
- 10Dental section, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkoknoi, Bangkok 10700, Thailand
- 11Medical Molecular Biotechnology Research Group, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathum Thani 12120, Thailand
- 12Dental Department, Samitivej Sukhumvit Hospital, Bangkok 10110, Thailand
- 13Division of Orthodontics, Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
- 14Fun Dee Clinic, Bangkok 10900, Thailand
- 15Orthodontic Section, Department of Preventive Dentistry, Faculty of Dentistry, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand
- 16Biomedical Sciences Division, King Abdullah University of Science and Technology Center of Excellence for Smart Health, King Abdullah University of Science and Technology, Thuwal 23955-6900, Kingdom of Saudi Arabia
- 17Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34093, Türkiye
- 18Division of Oral Anatomy, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan
Abstract
Primary cilia play an essential role in molecular signaling transduction during development, coordinating cell fate decisions and morphogenesis. Defects in components of the primary cilium result in an array of developmental syndromes called ciliopathies. Here we report 24 patients with nine rare and seven novel variants in the primary cilia gene C2CD3, which has previously been implicated in the ciliopathy Orofaciodigital syndrome XIV. Patients displayed an array of dental defects impacting the number, shape, and timing of tooth development. To understand the etiology underlying these defects, murine and avian models were analyzed during embryonic development. Ap2Cre;C2cd3ex4-5 fl/fl mouse mutants showed a range of dental defects prenatally, mimicking several of the phenotypes observed in patients. Shh was upregulated in the developing upper jaw, leading to a widening of the midline, while Shh expression in the lower jaw was reduced, highlighting the context-dependent impact of cilia on hedgehog signaling. In avian mutants carrying a C2CD3 variant, talpid2, tooth buds were evident with SHH expression upregulated during early development in both upper and lower jaws. Cartilage defects were additionally observed in both conditional mouse knockouts and talpid2 embryos. These changes in Shh signaling provide a mechanism to explain the phenotypes in patients and highlight the conserved role of C2CD3 in coordinating the morphogenetic potential of the jaw and patterning of the forming dentition. Given the conserved phenotypes, alterations in C2CD3-dependent ciliogenesis may have played a role in modulating Shh signaling to alter the timing and position of tooth germs across vertebrate evolution.
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BibTeX
@article{kantaputra2026c2cd3,
title = {{C2CD3 links tooth patterning to evolutionary tooth loss in birds and dental anomalies across vertebrates}},
author = {Piranit Kantaputra and Yeliz Guven and Narumon Bunpiem and Kimberly Cochran and Tengyang Qiu and Evan C. Brooks and Paisan Kangvonkit and Saisupee Arayasantiwong and Chumpol Ngamphiw and Sissades Tongsima and Puckpring Sompoprungroat and Nuttaporn Sengtae and Kanoknart Chintakanon and Saisinee Ngaohiranpat and Chidchanok Leetanakul and Stefan T. Arold and Tügba Kalayci and Katsushige Kawasaki and Atsushi Ohazama and Samantha A. Brugmann and Abigail S. Tucker},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2603057123},
url = {https://doi.org/10.1073/pnas.2603057123},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - C2CD3 links tooth patterning to evolutionary tooth loss in birds and dental anomalies across vertebrates
AU - Piranit Kantaputra
AU - Yeliz Guven
AU - Narumon Bunpiem
AU - Kimberly Cochran
AU - Tengyang Qiu
AU - Evan C. Brooks
AU - Paisan Kangvonkit
AU - Saisupee Arayasantiwong
AU - Chumpol Ngamphiw
AU - Sissades Tongsima
AU - Puckpring Sompoprungroat
AU - Nuttaporn Sengtae
AU - Kanoknart Chintakanon
AU - Saisinee Ngaohiranpat
AU - Chidchanok Leetanakul
AU - Stefan T. Arold
AU - Tügba Kalayci
AU - Katsushige Kawasaki
AU - Atsushi Ohazama
AU - Samantha A. Brugmann
AU - Abigail S. Tucker
PY - 2026
DA - 2026/10/28
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2603057123
UR - https://doi.org/10.1073/pnas.2603057123
AB - Primary cilia play an essential role in molecular signaling transduction during development, coordinating cell fate decisions and morphogenesis. Defects in components of the primary cilium result in an array of developmental syndromes called ciliopathies. Here we report 24 patients with nine rare and seven novel variants in the primary cilia gene C2CD3, which has previously been implicated in the ciliopathy Orofaciodigital syndrome XIV. Patients displayed an array of dental defects impacting the number, shape, and timing of tooth development. To understand the etiology underlying these defects, murine and avian models were analyzed during embryonic development. Ap2Cre;C2cd3ex4-5 fl/fl mouse mutants showed a range of dental defects prenatally, mimicking several of the phenotypes observed in patients. Shh was upregulated in the developing upper jaw, leading to a widening of the midline, while Shh expression in the lower jaw was reduced, highlighting the context-dependent impact of cilia on hedgehog signaling. In avian mutants carrying a C2CD3 variant, talpid2, tooth buds were evident with SHH expression upregulated during early development in both upper and lower jaws. Cartilage defects were additionally observed in both conditional mouse knockouts and talpid2 embryos. These changes in Shh signaling provide a mechanism to explain the phenotypes in patients and highlight the conserved role of C2CD3 in coordinating the morphogenetic potential of the jaw and patterning of the forming dentition. Given the conserved phenotypes, alterations in C2CD3-dependent ciliogenesis may have played a role in modulating Shh signaling to alter the timing and position of tooth germs across vertebrate evolution.
SN - 0027-8424
SN - 1091-6490
ER -