Maxillofacial Plastic and Reconstructive Surgery

Korean Association of Maxillofacial Plastic and Reconstructive Surgeons (대한악안면성형재건외과학회)
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Smad4 Mediated TGF-β/BMP Signaling in Tooth Formation Using Smad4 Conditional Knockout Mouse

치아 발생과정에서 Smad4의 역할

  • Yoon, Chi-Young (Department of Oral and Maxillofacial Surgery, Institute of Oral Bioscience, BK21 Program, School of Dentistry, Chonbuk National University) ;
  • Baek, Jin-A (Department of Oral and Maxillofacial Surgery, Institute of Oral Bioscience, BK21 Program, School of Dentistry, Chonbuk National University) ;
  • Cho, Eui-Sic (Department of Oral and Maxillofacial Surgery, Institute of Oral Bioscience, BK21 Program, School of Dentistry, Chonbuk National University) ;
  • Ko, Seung-O (Department of Oral and Maxillofacial Surgery, Institute of Oral Bioscience, BK21 Program, School of Dentistry, Chonbuk National University)
  • 윤지영 (전북대학교 치의학전문대학원 구강악안면외과학교실, 구강생체과학연구소, BK21사업) ;
  • 백진아 (전북대학교 치의학전문대학원 구강악안면외과학교실, 구강생체과학연구소, BK21사업) ;
  • 조의식 (전북대학교 치의학전문대학원 구강악안면외과학교실, 구강생체과학연구소, BK21사업) ;
  • 고승오 (전북대학교 치의학전문대학원 구강악안면외과학교실, 구강생체과학연구소, BK21사업)
  • Received : 2012.12.11
  • Accepted : 2013.03.19
  • Published : 2013.03.31
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Abstract

Purpose: Smad4 is a central mediator for transforming growth factor-${\beta}$/bone morphogenetic protein ($TGF-{\beta}/BMP$) signals, which are involved in regulating cranial neural crest cell formation, migration, proliferation, and fate determination. Accumulated evidences indicate that $TGF-{\beta}/BMP$ signaling plays key roles in the early tooth morphogenesis. However, their roles in the late tooth formation, such as cellular differentiation and matrix formation are not clearly understood. The objective of this study is to understand the roles of Smad4 in vivo during enamel and dentin formation through tissue-specific inactivation of Smad4. Methods: We generated and analyzed mice with dental epithelium-specific inactivation of the Smad4 gene (K14-Cre:$Smad4^{fl/fl}$) and dental mesenchyme-specific inactivation of Smad4 gene (Osr2Ires-Cre:$Smad4^{fl/fl}$). Results: In the tooth germs of K14-Cre:$Smad4^{fl/fl}$, ameloblast differentiation was not detectable in inner enamel epithelial cells, however, dentin-like structure was formed in dental mesenchymal cells. In the tooth germs of Osr2Ires-Cre:$Smad4^{fl/fl}$ mice, ameloblasts were normally differentiated from inner enamel epithelial cells. Interestingly, we found that bone-like structures, with cellular inclusion, were formed in the dentin region of Osr2Ires-Cre:$Smad4^{fl/fl}$ mice. Conclusion: Taken together, our study demonstrates that Smad4 plays a crucial role in regulating ameloblast and odontoblast differentiation, as well as in regulating epithelial-mesenchymal interactions during tooth development.

Keywords

References

  1. Mina M, Kollar EJ. The induction of odontogenesis in nondental mesenchyme combined with early murine mandibular arch epithelium. Arch Oral Biol 1987;32:123-7. https://doi.org/10.1016/0003-9969(87)90055-0
  2. Peters H, Neübuser A, Kratochwil K, Balling R. Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities. Genes Dev 1998;12:2735-47. https://doi.org/10.1101/gad.12.17.2735
  3. Wall NA, Hogan BL. TGF-beta related genes in development. Curr Opin Genet Dev 1994;4:517-22. https://doi.org/10.1016/0959-437X(94)90066-C
  4. Kingsley DM. The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev 1994;8:133-46. https://doi.org/10.1101/gad.8.2.133
  5. Massague J. How cells read TGF-beta signals. Nat Rev Mol Cell Biol 2000;1:169-78. https://doi.org/10.1038/35043051
  6. Yang X, Li C, Xu X, Deng C. The tumor suppressor SMAD4/DPC4 is essential for epiblast proliferation and mesoderm induction in mice. Proc Natl Acad Sci U S A 1998; 95:3667-72. https://doi.org/10.1073/pnas.95.7.3667
  7. Kwan KM. Conditional alleles in mice: practical considerations for tissue-specific knockouts. Genesis 2002;32:49-62. https://doi.org/10.1002/gene.10068
  8. Yang X, Li C, Herrera PL, Deng CX. Generation of Smad4/ Dpc4 conditional knockout mice. Genesis 2002;32:80-1. https://doi.org/10.1002/gene.10029
  9. Metzger D, Chambon P. Site- and time-specific gene targeting in the mouse. Methods 2001;24:71-80. https://doi.org/10.1006/meth.2001.1159
  10. Lan Y, Jiang R. Sonic hedgehog signaling regulates reciprocal epithelial-mesenchymal interactions controlling palatal outgrowth. Development 2009;136:1387-96. https://doi.org/10.1242/dev.028167
  11. Ko SO, Chung IH, Xu X, et al. Smad4 is required to regulate the fate of cranial neural crest cells. Dev Biol 2007;312:435-47. https://doi.org/10.1016/j.ydbio.2007.09.050
  12. Xu X, Jeong L, Han J, Ito Y, Bringas P Jr, Chai Y. Developmental expression of Smad1-7 suggests critical function of TGF-beta/BMP signaling in regulating epithelial-mesenchymal interaction during tooth morphogenesis. Int J Dev Biol 2003;47:31-9.
  13. Thesleff I. Epithelial-mesenchymal signalling regulating tooth morphogenesis. J Cell Sci 2003;116:1647-8. https://doi.org/10.1242/jcs.00410
  14. Thesleff I, Mikkola M. The role of growth factors in tooth development. Int Rev Cytol 2002;217:93-135. https://doi.org/10.1016/S0074-7696(02)17013-6
  15. Bègue-Kirn C, Smith AJ, Loriot M, Kupferle C, Ruch JV, Lesot H. Comparative analysis of TGF beta s, BMPs, IGF1, msxs, fibronectin, osteonectin and bone sialoprotein gene expression during normal and in vitro-induced odontoblast differentiation. Int J Dev Biol 1994;38:405-20.
  16. Fjeld K, Kettunen P, Furmanek T, Kvinnsland IH, Luukko K. Dynamic expression of Wnt signaling-related Dickkopf1, -2, and -3 mRNAs in the developing mouse tooth. Dev Dyn 2005;233:161-6. https://doi.org/10.1002/dvdy.20285
  17. Suomalainen M, Thesleff I. Patterns of Wnt pathway activity in the mouse incisor indicate absence of Wnt/beta-catenin signaling in the epithelial stem cells. Dev Dyn 2010;239:364-72.
  18. Jernvall J, Thesleff I. Reiterative signaling and patterning during mammalian tooth morphogenesis. Mech Dev 2000;92:19-29. https://doi.org/10.1016/S0925-4773(99)00322-6
  19. Cam Y, Neumann MR, Oliver L, Raulais D, Janet T, Ruch JV. Immunolocalization of acidic and basic fibroblast growth factors during mouse odontogenesis. Int J Dev Biol 1992;36:381-9.
  20. Ruch JV, Lesot H, Begue-Kirn C. Odontoblast differentiation. Int J Dev Biol 1995;39:51-68.
  21. Ruoslahti E, Yamaguchi Y. Proteoglycans as modulators of growth factor activities. Cell 1991;64:867-9. https://doi.org/10.1016/0092-8674(91)90308-L
  22. Thesleff I, Keranen S, Jernvall J. Enamel knots as signaling centers linking tooth morphogenesis and odontoblast differentiation. Adv Dent Res 2001;15:14-8. https://doi.org/10.1177/08959374010150010401
  23. Karcher-Djuricic V, Staubli A, Meyer JM, Ruch JV. Acellular dental matrices promote functional differentiation of ameloblasts. Differentiation 1985;29:169-75. https://doi.org/10.1111/j.1432-0436.1985.tb00311.x
  24. Ruch JV. Determinisms of odontogenesis. Revis Biol Celular 1987;14:1-99.