Mesenchymal Wnt/β-catenin signaling limits tooth number
Mesenchymal Wnt/β-catenin signaling limits tooth number
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DOI：
10.1242/dev.158048
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发表时间：
2018-02-15
期刊：
影响因子：
4.6
通讯作者：
Thesleff, Irma
中科院分区：
文献类型：
--
作者：
Jarvinen, Elina;Shimomura-Kuroki, Junko;Thesleff, Irma
牙齿发育不全是人类主要的发育异常之一，通常会影响连续牙齿形成所产生的恒牙列，并且在大多数情况下，是由扰乱上皮 Wnt/β-连环蛋白信号传导的突变引起的。此外，Wnt 反馈抑制剂 AXIN2 的功能丧失突变会导致人类牙齿发育不全。我们使用小鼠模型研究了 Wnt/β-catenin 信号在臼齿顺序形成过程中的功能。在口腔上皮中 Wnt/β-连环蛋白信号传导基因激活后观察到新牙齿的持续萌生，伴随着 Wnt 拮抗剂表达的增强和牙齿间质中 Wnt/β-连环蛋白信号传导的下调。间充质 Wnt/β-连环蛋白信号传导的遗传和药理学激活负向调节牙齿的顺序形成，这种效应部分由 Bmp4 介导。 Runx2 是一种基因，其功能缺失突变导致人类锁骨颅骨发育不良综合征中多生牙的连续形成，该基因抑制了牙齿间充质中 Wnt 抑制剂 Axin2 和 Drapc1 的表达。我们的数据表明，增加的间充质 Wnt 信号传导抑制牙齿的顺序形成，并表明 Axin2/Runx2 拮抗相互作用调节间充质 Wnt/β-catenin 信号传导的水平，这是人类 AXIN2 和 RUNX2 突变引起的对比牙齿表型的基础。
Tooth agenesis is one of the predominant developmental anomalies in humans, usually affecting the permanent dentition generated by sequential tooth formation and, in most cases, caused by mutations perturbing epithelial Wnt/beta-catenin signaling. In addition, loss-offunction mutations in the Wnt feedback inhibitor AXIN2 lead to human tooth agenesis. We have investigated the functions of Wnt/beta-catenin signaling during sequential formation of molar teeth using mouse models. Continuous initiation of new teeth, which is observed after genetic activation of Wnt/beta-catenin signaling in the oral epithelium, was accompanied by enhanced expression of Wnt antagonists and a downregulation of Wnt/beta-catenin signaling in the dental mesenchyme. Genetic and pharmacological activation of mesenchymal Wnt/beta-catenin signaling negatively regulated sequential tooth formation, an effect partly mediated by Bmp4. Runx2, a gene whose loss-of-function mutations result in sequential formation of supernumerary teeth in the human cleidocranial dysplasia syndrome, suppressed the expression of Wnt inhibitors Axin2 and Drapc1 in dental mesenchyme. Our data indicate that increased mesenchymal Wnt signaling inhibits the sequential formation of teeth, and suggest that Axin2/Runx2 antagonistic interactions modulate the level of mesenchymal Wnt/beta-catenin signaling, underlying the contrasting dental phenotypes caused by human AXIN2 and RUNX2 mutations.