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Molecular and Cellular Biology, November 2009, p. 5941-5951, Vol. 29, No. 21
0270-7306/09/$08.00+0 doi:10.1128/MCB.00706-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Disruption of Smad4 in Odontoblasts Causes Multiple Keratocystic Odontogenic Tumors and Tooth Malformation in Mice
Yuanrong Gao,1,2,
Guan Yang,1,
Tujun Weng,1
Juan Du,2
Xuejiu Wang,2
Jian Zhou,2
Songlin Wang,2,3* and
Xiao Yang1*
Genetic Laboratory of Development and Diseases, State Key Laboratory of Proteomics, Institute of Biotechnology, Beijing 100071, People's Republic of China,1 Salivary Gland Disease Center and Molecular Laboratory for Gene Therapy and Tooth Regeneration, Capital Medical University School of Stomatology, Beijing 100050, People's Republic of China,2 Department of Biochemistry and Molecular Biology, Capital Medical University School of Basic Medical Sciences, Beijing 100069, People's Republic of China3
Received 31 May 2009/ Returned for modification 3 July 2009/ Accepted 14 August 2009
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-β)/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-β/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.
* Corresponding author. Mailing adress for Xiao Yang: Institute of Biotechnology, 20 Dongdajie, Beijing 100071, People's Republic of China. Phone and fax: 86-10-63895937. E-mail: yangx{at}nic.bmi.ac.cn. Mailing address for Songlin Wang: Capital Medical University School of Stomatology, Tian Tan Xi Li No. 4, Beijing 100050, People's Republic of China. Phone and fax: 86-10-83911708. E-mail: slwang{at}ccmu.edu.cn
Published ahead of print on 24 August 2009.
Y.G. and G.Y. contributed equally to this work.
Molecular and Cellular Biology, November 2009, p. 5941-5951, Vol. 29, No. 21
0270-7306/09/$08.00+0 doi:10.1128/MCB.00706-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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