C2CD3 links tooth patterning to evolutionary tooth loss in birds and dental anomalies across vertebrates
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;C2cd3 ex4-5 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, talpid 2 , 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 talpid 2 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.
Authors
- Abigail Saffron Tucker (ORCID: https://orcid.org/0000-0001-8871-6094)
- Piranit Nik Kantaputra (ORCID: https://orcid.org/0000-0001-9841-0881)
- Paisan Kangvonkit
- Atsushi Ohazama (ORCID: https://orcid.org/0000-0002-3496-0347)
- Chumpol Ngamphiw (ORCID: https://orcid.org/0000-0002-8581-397X)
- Kanoknart Chintakanon
- Sissades Tongsima (ORCID: https://orcid.org/0000-0002-1491-1839)
- Stefan T. Arold (ORCID: https://orcid.org/0000-0001-5278-0668)
- Chidchanok Leethanakul (ORCID: https://orcid.org/0000-0002-4450-3393)
- Tuğba Kalaycı (ORCID: https://orcid.org/0000-0002-9963-5916)
- Yeliz Güven (ORCID: https://orcid.org/0000-0002-4637-6025)
- Evan C. Brooks (ORCID: https://orcid.org/0000-0003-4895-8296)
- Samantha A. Brugmann (ORCID: https://orcid.org/0000-0002-6860-6450)
- Kim Cochran (ORCID: https://orcid.org/0009-0001-4411-0653)
- Katsushige Kawasaki (ORCID: https://orcid.org/0009-0000-1816-1337)
- Nuttaporn Sengtae
- Narumon Bunpiem
- Puckpring Sompoprungroat
- Tengyang Qiu
- Saisinee Ngaohiranpat
- Saisupee Arayasantiwong
Institutions
- Cincinnati Children's Hospital Medical Center (US)
- Burapha University (TH)
- Prince of Songkla University (TH)
- National Science and Technology Development Agency (TH)
- Siriraj Hospital (TH)
- Mahidol University (TH)
- University of Dental Medicine (MM)
- Chiang Mai University (TH)
- University of Cincinnati (US)
- Istanbul University (TR)
- Niigata University (JP)
- King Abdullah University of Science and Technology (SA)
- National Center for Genetic Engineering and Biotechnology (TH)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2026-10-28
- DOI
- https://doi.org/10.1073/pnas.2603057123
- Primary Topic
- dental development and anomalies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Chiang Mai University
- King Abdullah University of Science and Technology
- Health Systems Research Institute
- National Institutes of Health
- Biotechnology and Biological Sciences Research Council
- Global Collaborative Research, King Abdullah University of Science and Technology