Dact2 represses PITX2 transcriptional activation and cell proliferation through Wnt/beta-catenin signaling during odontogenesis.
Dact2 represses PITX2 transcriptional activation and cell proliferation through Wnt/beta-catenin signaling during odontogenesis.
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DOI：
10.1371/journal.pone.0054868
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Amendt BA
中科院分区：
文献类型：
--
作者：
Li X;Florez S;Wang J;Cao H;Amendt BA
Dact蛋白属于Dapper/Frodo蛋白家族，在Wnt和TGFβ信号传导中作为细胞质衰减因子发挥作用。先前的研究表明，Dact1通过促进β-连环蛋白的降解是一种有效的Wnt信号传导抑制剂。我们报道了Dact2作为经典Wnt信号传导途径抑制剂的一种新机制，即通过与PITX2相互作用。PITX2是Wnt/β -连环蛋白信号传导中的下游转录因子，并且PITX2与Lef - 1协同激活下游基因。免疫组织化学验证了Dact2在牙上皮中的表达，这与Pitx2在上皮中的表达相关。Dact2功能缺失和PITX2功能获得的研究揭示了一种控制Dact2表达的反馈机制。Pitx2内源性地激活Dact2的表达，而Dact2反馈抑制Pitx2的转录活性。采用了Topflash报告系统，显示PITX2对Wnt信号传导的激活，这种激活被Dact2减弱。瞬时转染证明了Dact2在牙齿发育过程中对关键的牙上皮分化因子的抑制作用。Dact2显著抑制PITX2对Dlx2和釉原蛋白启动子的激活。多方面的证据得出结论，这种抑制是通过Dact2和Pitx2蛋白之间的物理相互作用实现的。Dact2功能缺失还显示由于Wnt下游基因细胞周期蛋白D1和细胞周期蛋白D2上调，细胞增殖增加。总之，我们已经确定了Dact2在胚胎牙齿发育中作为经典Wnt途径抑制剂的一种新作用，通过其对细胞增殖和分化的调节。
Dact proteins belong to the Dapper/Frodo protein family and function as cytoplasmic attenuators in Wnt and TGFβ signaling. Previous studies show that Dact1 is a potent Wnt signaling inhibitor by promoting degradation of β-catenin. We report a new mechanism for Dact2 function as an inhibitor of the canonical Wnt signaling pathway by interacting with PITX2. PITX2 is a downstream transcription factor in Wnt/β-catenin signaling, and PITX2 synergizes with Lef-1 to activate downstream genes. Immunohistochemistry verified the expression of Dact2 in the tooth epithelium, which correlated with Pitx2 epithelial expression. Dact2 loss of function and PITX2 gain of function studies reveal a feedback mechanism for controlling Dact2 expression. Pitx2 endogenously activates Dact2 expression and Dact2 feeds back to repress Pitx2 transcriptional activity. A Topflash reporter system was employed showing PITX2 activation of Wnt signaling, which is attenuated by Dact2. Transient transfections demonstrate the inhibitory effect of Dact2 on critical dental epithelial differentiation factors during tooth development. Dact2 significantly inhibits PITX2 activation of the Dlx2 and amelogenin promoters. Multiple lines of evidence conclude the inhibition is achieved by the physical interaction between Dact2 and Pitx2 proteins. The loss of function of Dact2 also reveals increased cell proliferation due to up-regulated Wnt downstream genes, cyclinD1 and cyclinD2. In summary, we have identified a novel role for Dact2 as an inhibitor of the canonical Wnt pathway in embryonic tooth development through its regulation of cell proliferation and differentiation.
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影响因子：
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