Inhibition of Wnt signaling by Wise (Sostdc1) and negative feedback from Shh controls tooth number and patterning
Inhibition of Wnt signaling by Wise (Sostdc1) and negative feedback from Shh controls tooth number and patterning
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DOI：
10.1242/dev.054668
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发表时间：
2010-10-01
期刊：
影响因子：
4.6
通讯作者：
Krumlauf, Robb
中科院分区：
文献类型：
--
作者：
Ahn, Youngwook;Sanderson, Brian W.;Krumlauf, Robb
携带Wise（Sostdc 1）突变的小鼠在牙齿发育的许多方面显示出缺陷，包括牙齿数量，大小和牙尖图案。为了了解这些缺陷的基础，我们研究了Wise在牙齿发育中调节的途径。我们提出的证据表明，在牙齿发育，怀斯抑制生存的间隙或门齿残芽作为抑制剂Lrp5和Lrp6依赖Wnt信号。减少Wnt共受体基因Lrp5和Lrp6的剂量可以挽救Wise无效的牙齿表型。Wise的失活导致Wnt信号升高，因此，正常无牙间隙区域中的残留牙芽显示增殖增加和持续发育以形成多生牙。相反，功能获得性研究表明，异位Wise减少了Wnt信号传导和牙齿数量。我们的分析表明，Fgf和Shh途径是Wise调节的Wnt信号传导的主要下游靶点。此外，我们的实验表明，Shh作为Wnt信号的负反馈调节器，从而决定了退化芽的命运和后来的牙齿图案。这些数据提供了深入了解牙齿发育中控制Wnt信号传导的机制，以及信号通路之间的串扰如何控制牙齿数量和形态发生。
Mice carrying mutations in Wise (Sostdc1) display defects in many aspects of tooth development, including tooth number, size and cusp pattern. To understand the basis of these defects, we have investigated the pathways modulated by Wise in tooth development. We present evidence that, in tooth development, Wise suppresses survival of the diastema or incisor vestigial buds by serving as an inhibitor of Lrp5- and Lrp6-dependent Wnt signaling. Reducing the dosage of the Wnt co-receptor genes Lrp5 and Lrp6 rescues the Wise-null tooth phenotypes. Inactivation of Wise leads to elevated Wnt signaling and, as a consequence, vestigial tooth buds in the normally toothless diastema region display increased proliferation and continuous development to form supernumerary teeth. Conversely, gain-of-function studies show that ectopic Wise reduces Wnt signaling and tooth number. Our analyses demonstrate that the Fgf and Shh pathways are major downstream targets of Wise-regulated Wnt signaling. Furthermore, our experiments revealed that Shh acts as a negative-feedback regulator of Wnt signaling and thus determines the fate of the vestigial buds and later tooth patterning. These data provide insight into the mechanisms that control Wnt signaling in tooth development and into how crosstalk among signaling pathways controls tooth number and morphogenesis.