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Mesenchymal Smad4 mediated signaling is essential for palate development

구개 형성과정에서 간엽 내 Smad4 매개 신호전달의 역할

  • Yoon, Chi-Young (Department of Oral and Maxillofacial Surgery, Institute of Oral Bioscience and BK21 program, School of Dentistry, Chonbuk National University) ;
  • Baek, Jin-A (Department of Oral and Maxillofacial Surgery, Institute of Oral Bioscience and BK21 program, School of Dentistry, Chonbuk National University) ;
  • Cho, Eui-Sic (Department of Oral and Maxillofacial Surgery, Institute of Oral Bioscience and BK21 program, School of Dentistry, Chonbuk National University) ;
  • Ko, Seung-O (Department of Oral and Maxillofacial Surgery, Institute of Oral Bioscience and 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 : 2010.09.26
  • Accepted : 2010.12.22
  • Published : 2010.12.31

Abstract

Introduction: A cleft palate is a common birth defect in humans with an incidence of 1/500 to 1/1,000 births. It appears to be caused by multiple genetic and environmental factors during palatogenesis. Many molecules are involved in palate formation but the biological mechanisms underlying the normal palate formation and cleft palate are unclear. Accumulating evidence suggests that transforming growth factor $\beta$/bone morphogenetic proteins (TGF-$\beta$/BMP) family members mediate the epithelial-mesenchymal interactions during palate formation. However, their roles in palatal morphogenesis are not completely understood. Materials and Methods: To understand the roles of TGF-$\beta$/BMP signaling in vivo during palatogenesis, mice with a palatal mesenchyme- specific deletion of Smad4, a key intracellular mediator of TGF-$\beta$/BMP signaling, were generated and analyzed using the Osr2Ires-Cre mice. Results: The mutant mice were alive at the time of birth with open eyelids and complete cleft palate but died within 24 hours after birth. In skeletal preparation, the horizontal processes of the palatine bones in mutants were not formed and resulted in a complete cleft palate. At E13.5, the palatal shelves of the mutants were growing as normally as those of theirwild type littermates. However, the palatal shelves of the mutants were not elevated at E14.5 in contrast to the elevated palatal shelves of the wild type mice. At E15.5, the palatal shelves of the mutants were elevated over the tongue but did not come in contact with each other, resulting in a cleft palate. Conclusion: These results suggest that mesenchymal Smad4 mediated signaling is essential for the growth of palatal processes and suggests that TGF-$\beta$/BMP family members are essential regulators during palate development.

Acknowledgement

Supported by : 한국연구재단

References

  1. Marazita ML, Field LL, Cooper ME, Tobias R, Maher BS, Peanchitlertkajorn S, et al. Genome scan for loci involved in cleft lip with or without cleft palate, in Chinese multiplex families. Am J Hum Genet 2002;71:349-64. https://doi.org/10.1086/341944
  2. Gritli-Linde A. Molecular control of secondary palate development. Dev Biol 2007;301:309-26. https://doi.org/10.1016/j.ydbio.2006.07.042
  3. Massague′J. How cells read TGF-$\beta$ signals. Nat Rev Mol Cell Biol 2000;1:169-78. https://doi.org/10.1038/35043051
  4. Weinstein M, Yang X, Deng C. Functions of mammalian Smad genes as revealed by targeted gene disruption in mice. Cytokine Growth Factor Rev 2000;11:49-58. https://doi.org/10.1016/S1359-6101(99)00028-3
  5. 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
  6. Ko SO, Chung IH, Xu X, Oka S, Zhao H, Cho ES, 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
  7. Lan Y, Ovitt CE, Cho ES, Maltby KM, Wang Q, Jiang R. Oddskipped related 2 (Osr2) encodes a key intrinsic regulator of secondary palate growth and morphogenesis. Development 2004; 131:3207-16. https://doi.org/10.1242/dev.01175
  8. 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
  9. 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
  10. Martin SJ, Newmeyer DD, Mathias S, Farschon DM, Wang HG, Reed JC, et al. Cell-free reconstitution of Fas-, UV radiation- and ceramide-induced apoptosis. EMBO J 1995;14:5191-200.
  11. Ferguson MWJ, Honig LS. Epithelial-mesenchymal interactions during vertebrate palatogenesis. Curr Top Dev Biol 1984;19:138-64.
  12. Dudas M, Kim J, Li WY, Nagy A, Larsson J, Karlsson S, et al. Epithelial and ectomesenchymal role of the type I TGF-$\beta$ receptor ALK5 during facial morphogenesis and palatal fusion. Dev Biol 2006;296:298-314. https://doi.org/10.1016/j.ydbio.2006.05.030
  13. Kaartinen V, Voncken JW, Shuler C, Warburton D, Bu D, Heisterkamp N, et al. Abnormal lung development and cleft palate in mice lacking TGF-$\beta$3 indicates defects of epithelialmesenchymal interaction. Nat Genet 1995;11:415-21. https://doi.org/10.1038/ng1295-415
  14. Liu W, Sun X, Braut A, Mishina Y, Behringer RR, Mina M, et al. Distinct functions for Bmp signaling in lip and palate fusion in mice. Development 2005;132:1453-61. https://doi.org/10.1242/dev.01676
  15. Rice R, Spencer-Dene B, Connor EC, Gritli-Linde A, McMahon AP, Dickson C, et al. Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate. J Clin Invest 2004;113:1692-700. https://doi.org/10.1172/JCI20384
  16. Satokata I, Maas R. Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nature Genet 1994;6:348-56. https://doi.org/10.1038/ng0494-348
  17. Zhao Y, Guo YJ, Tomac AC, Taylor NR, Grinberg A, Lee EJ, et al. Isolated cleft palate in mice with targeted mutation of the LIM homeobox gene Lhx8. Proc Natl Acad Sci U S A 1999;96:15002-6. https://doi.org/10.1073/pnas.96.26.15002
  18. Zhang Z, Song Y, Zhao X, Zhang X, Fermin C, Chen Y. Rescue of cleft palate in Msx1-deficient mice by transgenic Bmp4 reveals a network of BMP and Shh signaling in the regulation of mammalian palatogenesis. Development 2002;129:4135-46.
  19. Yu L, Gu S, Alappat S, Song Y, Yan M, Zhang X, et al. Shox2- deficient mice exhibit a rare type of incomplete clefting of the secondary palate. Development 2005;132:4397-406. https://doi.org/10.1242/dev.02013
  20. Ito Y, Yeo JY, Chytil A, Han J, Bringas P Jr, Nakajima A, et al. Conditional inactivation of Tgfbr2 in cranial neural crest causes cleft palate and calvaria defects. Development 2003;130:5269-80. https://doi.org/10.1242/dev.00708
  21. Xu X, Han J, Ito Y, Bringas P Jr, Urata MM, Chai Y. Cell autonomous requirement for Tgfbr2 in the disappearance of medial edge epithelium during palatal fusion. Dev Biol 2006;297:238- 48. https://doi.org/10.1016/j.ydbio.2006.05.014