ArticleMolecular and cellular biology2009
Disruption of Smad4 in odontoblasts causes multiple keratocystic odontogenic tumors and tooth malformation in mice.
Article in Molecular and cellular biology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 54 citations in OpenAlex.
- Depletion of macrophages during early postnatal development leads to disrupted tooth root development and altered Gli1⁺ MSC trajectory.Cell death & disease · 2026Article
- The Role of Genetics in Human Oral Health: A Systematic-Narrative Review.Dentistry journal · 2025Review
- Abnormal dental follicle cells: A crucial determinant in tooth eruption disorders (Review).Molecular medicine reports · 2024Review
- Atp6i deficient mouse model uncovers transforming growth factor-β1 /Smad2/3 as a key signaling pathway regulating odontoblast differentiation and tooth root formation.International journal of oral science · 2023Article
- TGF-β Signaling in Progression of Oral Cancer.International journal of molecular sciences · 2023Review
- BMP signaling in the development and regeneration of tooth roots: from mechanisms to applications.Frontiers in cell and developmental biology · 2023Review
- Odontoblast processes of the mouse incisor are plates oriented in the direction of growth.Anatomical record (Hoboken, N.J. : 2007) · 2021Article
- Cell dynamics in Hertwig's epithelial root sheath are regulated by β-catenin activity during tooth root development.Journal of cellular physiology · 2021Article
- Monitoring of canonical BMP and Wnt activities during postnatal stages of mouse first molar root formation.Journal of applied oral science : revista FOB · 2021Article
- Transforming Growth Factor-β Signaling Regulates Tooth Root Dentinogenesis by Cooperation With Wnt Signaling.Frontiers in cell and developmental biology · 2021Article
- Article
- [The role of bone morphogenetic protein signaling pathway in tooth root development].Hua xi kou qiang yi xue za zhi = Huaxi kouqiang yixue zazhi = West China journal of stomatology · 2018Review
- TGF-β Family Signaling in Epithelial Differentiation and Epithelial-Mesenchymal Transition.Cold Spring Harbor perspectives in biology · 2018Review
- Evaluation and Immunolocalization of BMP4 and FGF8 in Odontogenic Cyst and Tumors.Analytical cellular pathology (Amsterdam) · 2018Article
- Association between Altered Expression and Genetic Variations of Transforming Growth Factor β-Smad Pathway with Chronic Myeloid Leukemia.International journal of hematology-oncology and stem cell research · 2018Article
- The Impact of the Eda Pathway on Tooth Root Development.Journal of dental research · 2017Article
- The fate of Osterix-expressing mesenchymal cells in dental root formation and maintenance.Orthodontics & craniofacial research · 2017Article
- Cellular and molecular mechanisms of tooth root development.Development (Cambridge, England) · 2017Review
- Site-specific function and regulation of Osterix in tooth root formation.International endodontic journal · 2016Review
- The Dentin Sialoprotein (DSP) Domain Regulates Dental Mesenchymal Cell Differentiation through a Novel Surface Receptor.Scientific reports · 2016Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Keratocystic odontogenic tumors (KCOTs) are cystic epithelial neoplasias with a high recurrence rate. However, the molecular mechanisms underlying the initiation and progression of KCOTs are still largely unknown. Here, we show that specific ablation of Smad4 in odontoblasts unexpectedly resulted in spontaneous KCOTs in mice. The mutant mice exhibited malformed teeth characterized by fractured incisors and truncated molar roots. These abnormalities were mainly caused by disrupted odontoblast differentiation that led to irregular dentin formation. The cystic tumors arising from the reactivation of epithelial rests of Malassez (ERM), in which Smad4 remained intact, proliferated and formed stratified and differentiated squamous epithelia that exhibited a dramatic upregulation of Hedgehog signaling. Odontoblasts, which are responsive to transforming growth factor beta (TGF-beta)/bone morphogenetic protein (BMP) signals, may produce signal molecules to inhibit the activation of ERM. Indeed, we observed a downregulation of BMP signals from Smad4 mutant odontoblasts to the adjacent Hertwig's epithelial root sheath (HERS). Intriguingly, KCOTs frequently emerged from Smad4-deficient ERM in keratinocyte-specific Smad4 knockout mice, suggesting a novel mechanism in which reciprocal TGF-beta/BMP signaling between odontoblasts and HERS was required for tooth root development and suppression of KCOT formation. These findings provide insight into the genetic basis underlying KCOTs and have important implications for new directions in KCOT treatment.
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