Wnt/β-Catenin Regulates the Activity of Epiprofin/Sp6, SHH, FGF, and BMP to Coordinate the Stages of Odontogenesis.
Wnt/β-Catenin Regulates the Activity of Epiprofin/Sp6, SHH, FGF, and BMP to Coordinate the Stages of Odontogenesis.
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DOI：
10.3389/fcell.2016.00025
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发表时间：
2016
影响因子：
5.5
通讯作者：
Unda FJ
中科院分区：
文献类型：
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作者：
Aurrekoetxea M;Irastorza I;García-Gallastegui P;Jiménez-Rojo L;Nakamura T;Yamada Y;Ibarretxe G;Unda FJ
背景：我们利用体外牙齿发育模型，研究了GSK-3活性特异性抑制剂溴吲哚红肟试剂（BIO）在牙形成过程中过度激活Wnt/β-catenin通路的影响。结果：牙起始期Wnt/β-catenin通路过度激活可上调和异位表达参与口腔外胚成牙区划分的上皮标记物Sonic Hedgehog （Shh）、Epiprofin （Epfn）和成纤维细胞生长因子8 （Fgf8）。这一结果表明牙源性潜能的异位扩展。在牙齿形态发生过程中，成纤维细胞生长因子4 （Fgf4）、成纤维细胞生长因子10 （Fgf10）、肌段同源盒1 （Msx-1）、骨形态发生蛋白4 （Bmp4）和Dickkopf WNT信号通路抑制剂1 （Dkk-1）在BIO培养的第一磨牙中过表达。相反，无翼整合位点10b （Wnt-10b）和Shh的表达水平降低。此外，成牙细胞分化标志物Nestin和Epfn在生物处理磨牙的牙间质中出现异位过表达。此外，牙间质碱性磷酸酶活性增加，再次提示异常，异位间质细胞分化。最后，Bmp4下调Epfn在牙齿形态发生过程中的表达。结论：我们认为Epfn和β-catenin相互激活存在一个正反馈回路。这两种分子的平衡表达对牙齿的正常发育至关重要。我们提出Wnt、Bmp和Epfn之间可能存在联系，这将关键性地决定牙尖的正确模式以及成牙细胞和成釉细胞的分化。
Background: We used an in vitro tooth development model to investigate the effects of overactivation of the Wnt/β-catenin pathway during odontogenesis by bromoindirubin oxime reagent (BIO), a specific inhibitor of GSK-3 activity. Results: Overactivating the Wnt/β-catenin pathway at tooth initiation upregulated and ectopically expressed the epithelial markers Sonic Hedgehog (Shh), Epiprofin (Epfn), and Fibroblast growth factor8 (Fgf8), which are involved in the delimitation of odontogenic fields in the oral ectoderm. This result indicated an ectopic extension of the odontogenic potential. During tooth morphogenesis, Fibroblast growth factor4 (Fgf4), Fibroblast growth factor10 (Fgf10), Muscle segment homeobox 1 (Msx-1), Bone Morphogenetic protein 4 (Bmp4), and Dickkopf WNT signaling pathway inhibitor 1 (Dkk-1) were overexpressed in first molars cultured with BIO. Conversely, the expression levels of Wingless integration site 10b (Wnt-10b) and Shh were reduced. Additionally, the odontoblast differentiation markers Nestin and Epfn showed ectopic overexpression in the dental mesenchyme of BIO-treated molars. Moreover, alkaline phosphatase activity increased in the dental mesenchyme, again suggesting aberrant, ectopic mesenchymal cell differentiation. Finally, Bmp4 downregulated Epfn expression during dental morphogenesis. Conclusions: We suggest the presence of a positive feedback loop wherein Epfn and β-catenin activate each other. The balance of the expression of these two molecules is essential for proper tooth development. We propose a possible link between Wnt, Bmp, and Epfn that would critically determine the correct patterning of dental cusps and the differentiation of odontoblasts and ameloblasts.