BMP通路关键因子在人类牙胚组织中的表达检测
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摘要
人类牙齿的发育是一个相对比较复杂的过程,许多信号通路互相串联在一起,形成一个复杂的信号网络共同调控牙齿的发育过程。小鼠作为模式生物,其牙齿发育的调控机制已经研究的比较透彻,但是不同物种之间存在差异,至今为止,我们对人类牙齿发育过程中信号调控的过程仍不是十分清楚。为了弄清人类牙齿发生的分子机制,同时了解信号通路的调控模式,我们做了一些相应的基础研究。有文献报道在小鼠中敲除BMPRIA,阻断BMP信号会导致牙胚发育停留在蕾状期,还有众多文献表明BMP信号缺失导致牙齿发育异常,由此可见BMP信号对于调控牙齿发育是比较关键的。本实验研究了BMP信号通路的一些关键因子在人牙胚中的表达情况,这些基因包括BMP2, BMP7, SDAM4, BMPRIA, BMPRIB和BMPRII, noggin.通过对比相应时期小鼠基因的表达情况,我们发现在人类牙胚发育的分子调控过程中BMPRIB的表达与小鼠存在差异,而其余基因表达情况均与小鼠类似,我们可以推测是否在人类牙胚发育过程中BMPRIB受体而不是BMPRIA起到了关键的信号传递的作用。通过本实验可以进一步探讨调节牙齿发育过程的信号通路之间的相互作用关系。
The development of human teeth is a relatively complex process. Many signaling pathways work in tandem together to form a complex signaling network to mediate the process of tooth development. Mice as a model organism, the regμLation of tooth development has been thoroughly studied, but there is considerable differences between the different species. So far, of the human tooth development controlling process, the signal is still not very clear. We did a lot of experiments to understand the molecμLar mechanism of human teeth and signaling pathway model. It is reported that if BMPRlA is blocked, the blocked BMP signaling can cause tooth development remain in the bud stage. There are numerous literature indicates that lacking of BMP signaling resμLts in abnormal tooth development. Therefore, BMP signaling is critical in the regμLation of tooth development. This experiment studies the key factors of the BMP signaling pathway in the expression of human tooth in these genes, including BMP2, BMP7, SDAM4, BMPR1A, BMPRIB and BMPRⅡ, NOGGIN. By comparing the corresponding period of gene expression in mice, we found BMPRIB expression in human tooth development is different in mice, while the rest were similar. We specμLate that it is not the BMPRIB but BMPRlA receptor plays a key role in signal transduction in human tooth germ development. This experiment can be further explored by adjusting the process of tooth development the interaction between signaling pathways.
The development of human teeth is a relatively complex process. Many signaling pathways work in tandem together to form a complex signaling network to mediate the process of tooth development. Mice as a model organism, the regμLation of tooth development has been thoroughly studied, but there is considerable differences between the different species. So far, of the human tooth development controlling process, the signal is still not very clear. We did a lot of experiments to understand the molecμLar mechanism of human teeth and signaling pathway model. It is reported that if BMPRlA is blocked, the blocked BMP signaling can cause tooth development remain in the bud stage. There are numerous literature indicates that lacking of BMP signaling resμLts in abnormal tooth development. Therefore, BMP signaling is critical in the regμLation of tooth development. This experiment studies the key factors of the BMP signaling pathway in the expression of human tooth in these genes, including BMP2, BMP7, SDAM4, BMPR1A, BMPRIB and BMPRⅡ, NOGGIN. By comparing the corresponding period of gene expression in mice, we found BMPRIB expression in human tooth development is different in mice, while the rest were similar. We specμLate that it is not the BMPRIB but BMPRlA receptor plays a key role in signal transduction in human tooth germ development. This experiment can be further explored by adjusting the process of tooth development the interaction between signaling pathways.
引文
[1].郑莉琴,戴银清,张彦定.牙齿发育与再生[J].组织工程与重建外科杂志.2007,3(1)：1-6.
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[3]. Irma Thesleff, Soile Keranen, Jukka Jernvall. Enamel Knots as Signaling Centers Linking Tooth Morphogenesis and Odontoblast Differentiation[J]. Adv Dent Res.2001,15:14-18.
[4]. Thesleff I, Keranen S, Jemvat 1 J.Enamel knots as signaling centers linking tooth morphogenesis and odontoblast differentiation [J]. Adv Dent Res,2001,15(8): 14-18.
[5]. Kollar, E.J, and Baird, G.R. Tissue interaction in embryonic mouse tooth germs[J]. J. Embryol. Exp. Morphol.1970,24,173-186.
[6]. Yan Ding ZHANG, Zhi CHEN, Yi Qiang SONG,et al. Making a tooth:growth factors, transcription factors, and stem cells[J]. Cell Research. 2005,15(5):301-316.
[7]. Thesleff I, Vaahtokari A, Partanen AM. Regu Lation of organogenesis. Common molecular mechanisms regu Lating the development of teeth and other organs[J]. Int J Dev Biol,1995,39:35-50.
[8]. Thesleff I, Mikkola M. The role of growth factors in tooth development[J]. Int Rev Cytol,2002,217:93-135.
[9]. Thesleff I.,Mikkola M. The role of growth factors in tooth development[J]. Int. Rev. Cytol,2002,217:93-135.
[10].Kettunen P, Thesleff I. Expression and function of FGFs-4,-8, and-9 suggest functional redundancy and repetitive use as epithelial signals during tooth morphogenesis[J]. Dev Dyn,1998,211:256-68.
[11]. Kratochwil K, Galceran J, et al. FGF4, a direct target of LEF1 and Wnt signaling, can rescue the arrest of tooth organogenesis in Lefl(-/-) mice[J]. Genes Dev,2002, 16:3173-3185.
[12].Min H, Danilenko DM, ScuLly SA, et al. Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless[J]. Genes Dev.1998; 12:3156-61.
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[16].Hardcastle Z, Mo R.Hui CC, et al. The Shh signaling pathway in tooth development:defects in Gli2 and Gli3 mutants[J]. Development.1998,125(15): 2803-2811.
[17]. Gordon M D, Nusse R. Wnt signaling:multiple pathways, multiple receptors, and multiple transcription factors[J]. J Biol Chem,2006,281(32):29-33.
[18].Clevers H. Wnt/b-catenin signaling in development and disease[J]. Cell,2006, 127(3):469-480.
[19].Huelsken J, Behrens J. The Wnt signalling pathway[J]. J Cell Sci.,2002,115: 3977-3978.
[20]. Liu P, Wakamiya M, Shea MJ, et al. Requirement for Wnt3 in vertebrate axis formation[J]. Nat Genet,1999,22:361-5.
[21].Huelsken J., Birchmeier. New aspects of Wnt signaling pathways in higher vertebrates[J]. Curr Din Genet Dev,2001,11(5):47-553.
[22]. Kohei Miyazono, Yuto Kamiya, Masato Morikawa. Bone morphogenetic protein receptors and signal transduction[J]. J. Biochem.2010,147(1):35-51.
[23]. Di Chen, Ming Zhao, Gregory R.Mundy. Bone Morphogenetic Proteins[J]. Growth Factors.2004,22(4):233-241.
[24]. P. Geetha-Loganathan, S.Nimmagadda, R.Huang, et al. Expression pattern of BMPs during chick limb development[J]. AnatEmbryol.2006,211:87-93.
[25].Xuguang Nie, Keuo Luukko, Paivi Kettunen. BMP signalling in craniofacial development [J]. Int. J.2006,50:511-521.
[26]. David, L., Mallet, C., Mazerbourg, S., Feige, J.J., and Bailly, S. Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells[J]. Blood,2007,109,1953-1961.
[27]..Abigail S. Tucker, et al. Transformation of Tooth Type Induced by Inhibition of BMP Signaling [J]. Science.1998,282:1136-1138.
[28]. Elisabetta Gazzerro, ErnestoCanalis. Bone morphogenetic proteins and their antagonists [J]. Rev Endocr Metab Disord.2006,7:51-66.
[29]. Yu, P.B., Beppu, H., Kawai, N., Li, E., and Bloch, K.D. Bone morphogenetic protein (BMP) type II receptor deletion reveals BMP ligand-specific gain of signaling in pulmonary artery smooth muscle cells [J]. J. Biol. Chem.2005,280, 24443-24450.
[30]. ten Dijke, P., Yamashita, H., Sampath, T.K.,Reddi, A.H., Estevez, M., Riddle, D.L., Ichijo, H.,Heldin, C.-H., and Miyazono, K.dentification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4 [J]. J. Biol. Chem. 1994,269,16985-16988.
[31].Nishitoh, H., Ichijo, H., Kimura, M., Matsumoto, T.,Makishima, F., Yamaguchi, A., Yamashita, H.,Enomoto, S., and Miyazono, K. Identification of type I and type II serine/threonine kinase receptors for growth/differentiation factor-5[J]. J. Biol. Chem.1996,271,21345-21352.
[32]. Kirsch, T., Nickel, J., and Sebald, W.BMP-2 antagonists emerge from alterations in the low-affinity binding epitope for receptor BMPR-II[J]. EMBO J. 2000,19,3314-3324.
[33]. Daly, A.C., Randall, R.A., and Hill, C.S.Transforming growth factor b-induced Smadl/5 phosphorylation in epithelial cells is mediated by novel receptor complexes and is essential for anchorage-independent growth. Mol[J]. Cell. Biol. 2008,28,6889-6902.
[34]. Shi, W., Chang, C., Nie, S., Xie, S., Wan, M., and Cao, X.Endofin acts as a Smad anchor for receptor activation in BMP signaling[J]. J. Cell Sci.2007,120,1216-1224.
[35]. Shi, Y., Wang, Y.F., Jayaraman, L., Yang, H.,Massague, J., and Pavletich, N.P.Crystal structure of a SmadMHl domain bound to DNA:Insights on DNA binding in TGF-b signaling[J]. Cell.1998,94,585-594.
[36]. Zhang, S., Fei, T., Zhang, L., et al. Smad7 antagonizes transforming growth factor b signaling in the nucleus by interfering with functional Smad-DNA complex formation[J]. Mol.Cell. Biol.2007,27:4488-4499.
[37].Ishida, W., Hamamoto, K., Kusanagi, K., Yagi, K.,Kawabata, M., Takehara, K., Sampath, T.K.,Kato, M., and Miyazono, K. Smad6 is a Smad1/5-induced Smad inhibitor:Characterization of bone morphogenetic protein-responsive element in the mouse Smad6 promoter[J]. J. Biol. Chem.2000,275,6075-6079.
[38].金岩综.牙齿与骨形成蛋白(BMP)的关系[J].国外医学口腔医学分册.1992,6：342-346.
[39]. Abigail S. Tucker, et al. Transformation of Tooth Type Induced by Inhibition of BMP Signaling [J]. Science.1998,282:1136-1138.
[40].葛成,杨连甲,刘宝林,等.BMP信号调控研究进展[J].国外医学·生理、病理科学与临床分册.2002,22(3)：257-259.
[41]. Annette Neubuser, HeikoPeters, RudiBalling, et al. Antagonistic Interactions between FGF and BMP Signaling Pathways:A Mechanism for Positioning the Sites of Tooth Formation[J]. Cell.1997,90:247-255.
[42]. Akihiro Hosoya, Ji-YounKim, Sung-WonCho, et al. BMP4 signaling regulates form ation of Hertwig's epithelial root sheath during tooth root development.[J]. Cell Tissue Res.2008,333:503-509.
[43]. P. Geetha-Loganathan, S.Nimmagadda, R.Huang, et al. Expression pattern of BMPs during chick limb development[J]. AnatEmbryol.2006,211:87-93.
[44]. Wei Liu, Xiaoxia Sun, Alen Braut, et al. Distinct functions for Bmp signaling in lip and palate fusion in mice[J]. Development and disease.2005,132:1453-1461.
[45]. Vainio S, Karavanova I. Jowett A, et al. Identification of BMP-4 as a signal mediating sec-ondary induction between epithelial and mesenchymal tissues during early tooth development [J]. Cell.1993.75:45-58.
[46].Bei M, Maas R. FGFs and BMP4 induce both Msxl-independent and Msxl- dependent signa-ling pathways in early tooth development [J]. Development,1998, 125:4325-4333.
[47]. St.Amand TR, Zhang Y, Semina EV, et al. Antagonistic signals between BMP4 and FGF8 define the expression of Pitxl and Pitx2 in mouse tooth-forming anlage. Dev Biol,2000,217:323-32.
[48]. Annette Neubuser, Heiko Peters, Rudi Balling, et al. Antagonistic Interactions between FGF and BMP Signaling Pathways:A Mechanism for Positioning the Sites of Tooth Formation [J]. Cell,1997,25 (90),247-255.
[49].Kratochwil K, DuLl M, Farinas I, et al. Lefl expression is activated by BMP-4 and regulates inductive tissue interactions in tooth and hair development. Genes Dev,1996,10:1382-94.
[50]. Luli, Minkui Lin,YingWang, et al. Bmprla is requird in mesenchymal tissue and has limited redundant function with Bmprlb in tooth and palate development[J]. Developmental Biology.2010.
[51].Xun Xu, Jun Han, Yoshihiro Ito, et al. Ectodermal Smad4 and p38 MAPK Are Functionally Redundant in Mediating TGF-/BMP Signaling During Tooth and Palate Development[J]. Developmental Cell.2008,15:322-329.
[52].Matsuo, T., Sugita, T., Kubo, T., Yasunaga, Y., Ochi, M. and Murakami,T. Injectable magnetic liposomes as a novel carrier ofrecombinant human BMP-2 for bone formation in a rat bone-defect model, J. Biomed. Mater[J]. Res.2003,66A, 747-754.
[53]. Murakami, N., Saito, N., Horiuchi, H., Okada, T., Nozaki, K. and Takaoka, K. Repair of segmental defects in rabbit humeri with titanium fiber mesh cylinders containing recombinant human bone morphogenetic protein-2 (rhBMP-2) and a synthetic polymer[J],J. Biomed. Mater. Res.2002,62,169-174.
[54].Thesleff, I. and Hurmerinta, K. Tissue interactions in tooth development[J]. Differentiation,1981,18,75-88.
[55]. Kratochwil K, Galceran J, et al. FGF4, a direct target of LEFl and Wnt signaling, can rescue the arrest of tooth organogenesis in Lefl(-/-) mice[J]. Genes Dev.,2002, 16:3173-3185.
[56]. Peters H, Neubuser A, et al. Pax9-deficient mice lack pharyngeal pouch derivatives and teech and exhibit craniofacial and limb abnormalities[J]. Genes Dev.,1998,12:2735-2747.
[57]. Neubuser A., Peters H., et al. Antagonistic interactions between FGF and BMP4 signaling pathways:A mechanism for positioning the sites of tooth formation[J]. Cell,1997,90:147-155.
[58]. Thesleff I., Paul Sharpe. Signalling networks regulating dental development[J]. Mechanisms of Development,1997,67:111-123.
[59]. Zhang Y, Zhang Z, Zhao X, et al. A new function of BMP4:dual role for BMP4 in regulation of Sonic hedgehog expression in the mouse tooth germ[J]. Development, 2000,127:1431-43.
[60]. Cobourne MT, Hardcastle Z, Sharpe PT. Sonic hedgehog regulates epithelial proliferation and cell survival in the developing tooth germ[J]. J Dent Res, 2001,80:1974-9.
[61].Mohler J. Requirements for hedgehog, a segmental polarity gene, in patterning larval and adult cuticle of Drosophila[J]. Genetics,1988,120(10):61-72.
[2]. Chai Y, Jiang X, Ito Y, et al. Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis[J]. Development,2000,127:1671-9.
[3]. Irma Thesleff, Soile Keranen, Jukka Jernvall. Enamel Knots as Signaling Centers Linking Tooth Morphogenesis and Odontoblast Differentiation[J]. Adv Dent Res.2001,15:14-18.
[4]. Thesleff I, Keranen S, Jemvat 1 J.Enamel knots as signaling centers linking tooth morphogenesis and odontoblast differentiation [J]. Adv Dent Res,2001,15(8): 14-18.
[5]. Kollar, E.J, and Baird, G.R. Tissue interaction in embryonic mouse tooth germs[J]. J. Embryol. Exp. Morphol.1970,24,173-186.
[6]. Yan Ding ZHANG, Zhi CHEN, Yi Qiang SONG,et al. Making a tooth:growth factors, transcription factors, and stem cells[J]. Cell Research. 2005,15(5):301-316.
[7]. Thesleff I, Vaahtokari A, Partanen AM. Regu Lation of organogenesis. Common molecular mechanisms regu Lating the development of teeth and other organs[J]. Int J Dev Biol,1995,39:35-50.
[8]. Thesleff I, Mikkola M. The role of growth factors in tooth development[J]. Int Rev Cytol,2002,217:93-135.
[9]. Thesleff I.,Mikkola M. The role of growth factors in tooth development[J]. Int. Rev. Cytol,2002,217:93-135.
[10].Kettunen P, Thesleff I. Expression and function of FGFs-4,-8, and-9 suggest functional redundancy and repetitive use as epithelial signals during tooth morphogenesis[J]. Dev Dyn,1998,211:256-68.
[11]. Kratochwil K, Galceran J, et al. FGF4, a direct target of LEF1 and Wnt signaling, can rescue the arrest of tooth organogenesis in Lefl(-/-) mice[J]. Genes Dev,2002, 16:3173-3185.
[12].Min H, Danilenko DM, ScuLly SA, et al. Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless[J]. Genes Dev.1998; 12:3156-61.
[13]. Sekine K, Ohuchi H, Fujiwara M, et al. Fgf10 is essential for limb and lung formation[J]. Nat Genet.1999; 21:138-41.
[14].Nybakken K, Perrimon. Hedgehog singnal transduction:recent findings. Curr Opin Genet [J]. Dev.2002,12(5):591-596.
[15]. INGHAM P W, MCMAHON A P. Hedgehog signaling in animal development: Paradigms and principles(Review) [J].Genes Dev,2001,15(23):3059-3087.
[16].Hardcastle Z, Mo R.Hui CC, et al. The Shh signaling pathway in tooth development:defects in Gli2 and Gli3 mutants[J]. Development.1998,125(15): 2803-2811.
[17]. Gordon M D, Nusse R. Wnt signaling:multiple pathways, multiple receptors, and multiple transcription factors[J]. J Biol Chem,2006,281(32):29-33.
[18].Clevers H. Wnt/b-catenin signaling in development and disease[J]. Cell,2006, 127(3):469-480.
[19].Huelsken J, Behrens J. The Wnt signalling pathway[J]. J Cell Sci.,2002,115: 3977-3978.
[20]. Liu P, Wakamiya M, Shea MJ, et al. Requirement for Wnt3 in vertebrate axis formation[J]. Nat Genet,1999,22:361-5.
[21].Huelsken J., Birchmeier. New aspects of Wnt signaling pathways in higher vertebrates[J]. Curr Din Genet Dev,2001,11(5):47-553.
[22]. Kohei Miyazono, Yuto Kamiya, Masato Morikawa. Bone morphogenetic protein receptors and signal transduction[J]. J. Biochem.2010,147(1):35-51.
[23]. Di Chen, Ming Zhao, Gregory R.Mundy. Bone Morphogenetic Proteins[J]. Growth Factors.2004,22(4):233-241.
[24]. P. Geetha-Loganathan, S.Nimmagadda, R.Huang, et al. Expression pattern of BMPs during chick limb development[J]. AnatEmbryol.2006,211:87-93.
[25].Xuguang Nie, Keuo Luukko, Paivi Kettunen. BMP signalling in craniofacial development [J]. Int. J.2006,50:511-521.
[26]. David, L., Mallet, C., Mazerbourg, S., Feige, J.J., and Bailly, S. Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells[J]. Blood,2007,109,1953-1961.
[27]..Abigail S. Tucker, et al. Transformation of Tooth Type Induced by Inhibition of BMP Signaling [J]. Science.1998,282:1136-1138.
[28]. Elisabetta Gazzerro, ErnestoCanalis. Bone morphogenetic proteins and their antagonists [J]. Rev Endocr Metab Disord.2006,7:51-66.
[29]. Yu, P.B., Beppu, H., Kawai, N., Li, E., and Bloch, K.D. Bone morphogenetic protein (BMP) type II receptor deletion reveals BMP ligand-specific gain of signaling in pulmonary artery smooth muscle cells [J]. J. Biol. Chem.2005,280, 24443-24450.
[30]. ten Dijke, P., Yamashita, H., Sampath, T.K.,Reddi, A.H., Estevez, M., Riddle, D.L., Ichijo, H.,Heldin, C.-H., and Miyazono, K.dentification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4 [J]. J. Biol. Chem. 1994,269,16985-16988.
[31].Nishitoh, H., Ichijo, H., Kimura, M., Matsumoto, T.,Makishima, F., Yamaguchi, A., Yamashita, H.,Enomoto, S., and Miyazono, K. Identification of type I and type II serine/threonine kinase receptors for growth/differentiation factor-5[J]. J. Biol. Chem.1996,271,21345-21352.
[32]. Kirsch, T., Nickel, J., and Sebald, W.BMP-2 antagonists emerge from alterations in the low-affinity binding epitope for receptor BMPR-II[J]. EMBO J. 2000,19,3314-3324.
[33]. Daly, A.C., Randall, R.A., and Hill, C.S.Transforming growth factor b-induced Smadl/5 phosphorylation in epithelial cells is mediated by novel receptor complexes and is essential for anchorage-independent growth. Mol[J]. Cell. Biol. 2008,28,6889-6902.
[34]. Shi, W., Chang, C., Nie, S., Xie, S., Wan, M., and Cao, X.Endofin acts as a Smad anchor for receptor activation in BMP signaling[J]. J. Cell Sci.2007,120,1216-1224.
[35]. Shi, Y., Wang, Y.F., Jayaraman, L., Yang, H.,Massague, J., and Pavletich, N.P.Crystal structure of a SmadMHl domain bound to DNA:Insights on DNA binding in TGF-b signaling[J]. Cell.1998,94,585-594.
[36]. Zhang, S., Fei, T., Zhang, L., et al. Smad7 antagonizes transforming growth factor b signaling in the nucleus by interfering with functional Smad-DNA complex formation[J]. Mol.Cell. Biol.2007,27:4488-4499.
[37].Ishida, W., Hamamoto, K., Kusanagi, K., Yagi, K.,Kawabata, M., Takehara, K., Sampath, T.K.,Kato, M., and Miyazono, K. Smad6 is a Smad1/5-induced Smad inhibitor:Characterization of bone morphogenetic protein-responsive element in the mouse Smad6 promoter[J]. J. Biol. Chem.2000,275,6075-6079.
[38].金岩综.牙齿与骨形成蛋白(BMP)的关系[J].国外医学口腔医学分册.1992,6：342-346.
[39]. Abigail S. Tucker, et al. Transformation of Tooth Type Induced by Inhibition of BMP Signaling [J]. Science.1998,282:1136-1138.
[40].葛成,杨连甲,刘宝林,等.BMP信号调控研究进展[J].国外医学·生理、病理科学与临床分册.2002,22(3)：257-259.
[41]. Annette Neubuser, HeikoPeters, RudiBalling, et al. Antagonistic Interactions between FGF and BMP Signaling Pathways:A Mechanism for Positioning the Sites of Tooth Formation[J]. Cell.1997,90:247-255.
[42]. Akihiro Hosoya, Ji-YounKim, Sung-WonCho, et al. BMP4 signaling regulates form ation of Hertwig's epithelial root sheath during tooth root development.[J]. Cell Tissue Res.2008,333:503-509.
[43]. P. Geetha-Loganathan, S.Nimmagadda, R.Huang, et al. Expression pattern of BMPs during chick limb development[J]. AnatEmbryol.2006,211:87-93.
[44]. Wei Liu, Xiaoxia Sun, Alen Braut, et al. Distinct functions for Bmp signaling in lip and palate fusion in mice[J]. Development and disease.2005,132:1453-1461.
[45]. Vainio S, Karavanova I. Jowett A, et al. Identification of BMP-4 as a signal mediating sec-ondary induction between epithelial and mesenchymal tissues during early tooth development [J]. Cell.1993.75:45-58.
[46].Bei M, Maas R. FGFs and BMP4 induce both Msxl-independent and Msxl- dependent signa-ling pathways in early tooth development [J]. Development,1998, 125:4325-4333.
[47]. St.Amand TR, Zhang Y, Semina EV, et al. Antagonistic signals between BMP4 and FGF8 define the expression of Pitxl and Pitx2 in mouse tooth-forming anlage. Dev Biol,2000,217:323-32.
[48]. Annette Neubuser, Heiko Peters, Rudi Balling, et al. Antagonistic Interactions between FGF and BMP Signaling Pathways:A Mechanism for Positioning the Sites of Tooth Formation [J]. Cell,1997,25 (90),247-255.
[49].Kratochwil K, DuLl M, Farinas I, et al. Lefl expression is activated by BMP-4 and regulates inductive tissue interactions in tooth and hair development. Genes Dev,1996,10:1382-94.
[50]. Luli, Minkui Lin,YingWang, et al. Bmprla is requird in mesenchymal tissue and has limited redundant function with Bmprlb in tooth and palate development[J]. Developmental Biology.2010.
[51].Xun Xu, Jun Han, Yoshihiro Ito, et al. Ectodermal Smad4 and p38 MAPK Are Functionally Redundant in Mediating TGF-/BMP Signaling During Tooth and Palate Development[J]. Developmental Cell.2008,15:322-329.
[52].Matsuo, T., Sugita, T., Kubo, T., Yasunaga, Y., Ochi, M. and Murakami,T. Injectable magnetic liposomes as a novel carrier ofrecombinant human BMP-2 for bone formation in a rat bone-defect model, J. Biomed. Mater[J]. Res.2003,66A, 747-754.
[53]. Murakami, N., Saito, N., Horiuchi, H., Okada, T., Nozaki, K. and Takaoka, K. Repair of segmental defects in rabbit humeri with titanium fiber mesh cylinders containing recombinant human bone morphogenetic protein-2 (rhBMP-2) and a synthetic polymer[J],J. Biomed. Mater. Res.2002,62,169-174.
[54].Thesleff, I. and Hurmerinta, K. Tissue interactions in tooth development[J]. Differentiation,1981,18,75-88.
[55]. Kratochwil K, Galceran J, et al. FGF4, a direct target of LEFl and Wnt signaling, can rescue the arrest of tooth organogenesis in Lefl(-/-) mice[J]. Genes Dev.,2002, 16:3173-3185.
[56]. Peters H, Neubuser A, et al. Pax9-deficient mice lack pharyngeal pouch derivatives and teech and exhibit craniofacial and limb abnormalities[J]. Genes Dev.,1998,12:2735-2747.
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