Disruption of Smad4 in odontoblasts causes multiple keratocystic odontogenic tumors and tooth malformation in mice.
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.
Gao
Yuanrong
Y
Genetic Laboratory of Development and Diseases, State Key Laboratory of Proteomics, Institute of Biotechnology, Beijing 100071, People's Republic of China.
Yang
Guan
G
Weng
Tujun
T
Du
Juan
J
Wang
Xuejiu
X
Zhou
Jian
J
Wang
Songlin
S
Yang
Xiao
X
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation; D003804:Dentin / Q000002:abnormalities / Q000473:pathology / Q000648:ultrastructure; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D018390:Gene Targeting; D019426:Integrases / Q000378:metabolism; D051379:Mice; D009804:Odontoblasts / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D009807:Odontogenic Cysts / Q000150:complications* / Q000473:pathology; D009808:Odontogenic Tumors / Q000150:complications* / Q000473:pathology; D015675:Osteocalcin / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction; D051901:Smad4 Protein / Q000378:metabolism*; D014071:Tooth Abnormalities / Q000150:complications* / Q000473:pathology; D014092:Tooth Root / Q000002:abnormalities / Q000473:pathology / Q000648:ultrastructure; D016212:Transforming Growth Factor beta / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D016212:Transforming Growth Factor beta; D015675:Osteocalcin; C045073:Cre recombinase; D019426:Integrases
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