SMAD4-mediated WNT signaling controls the fate of cranial neural crest cells during tooth morphogenesis
SMAD4-mediated WNT signaling controls the fate of cranial neural crest cells during tooth morphogenesis
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DOI：
10.1242/dev.061341
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发表时间：
2011-05-15
期刊：
影响因子：
4.6
通讯作者：
Chai, Yang
中科院分区：
文献类型：
--
作者：
Li, Jingyuan;Huang, Xiaofeng;Chai, Yang
在牙齿和颌骨形成过程中，转化生长因子β/骨形态发生蛋白信号调节多潜能颅神经嵴细胞的命运，因为这些细胞分别分化为成牙本质细胞和成骨细胞。Smad4是转化生长因子β/骨形态发生蛋白信号的共同介导者，其在调控细胞命运中的功能意义尚不清楚。在这项研究中，我们研究了Smad4通过组织特异性失活Smad4来调节牙间充质细胞命运的机制。Smad4的消融导致成牙本质细胞分化和牙本质形成的缺陷。此外，在OSR2-IresCre；Smad4(fl/fl)小鼠的牙齿中，异位类骨结构取代了正常的牙本质。尽管缺乏牙本质，OSR2-IresCre；Smad4(fl/fl)小鼠的釉质形成似乎没有受到影响，挑战了釉质发育的启动依赖于正常牙本质形成的范式。在分子水平上，Smad4的缺失导致WNT途径抑制物Dkk1和SFRP1的下调，以及规范的WNT信号的上调，包括β-连环素活性的增加。更重要的是，在体外抑制OSR2-IresCre；Smad4(f1/f1)牙间充质细胞上调的规范WNT通路部分挽救了CnC细胞命运的改变。综上所述，我们的研究表明，Smad4在调节转化生长因子β/骨形态发生蛋白和WNT信号之间的相互作用中发挥着至关重要的作用，以确保在器官发生过程中正确地决定数控细胞的命运。
TGF beta/BMP signaling regulates the fate of multipotential cranial neural crest (CNC) cells during tooth and jawbone formation as these cells differentiate into odontoblasts and osteoblasts, respectively. The functional significance of SMAD4, the common mediator of TGF beta/BMP signaling, in regulating the fate of CNC cells remains unclear. In this study, we investigated the mechanism of SMAD4 in regulating the fate of CNC-derived dental mesenchymal cells through tissue-specific inactivation of Smad4. Ablation of Smad4 results in defects in odontoblast differentiation and dentin formation. Moreover, ectopic bone-like structures replaced normal dentin in the teeth of Osr2-IresCre;Smad4(fl/fl) mice. Despite the lack of dentin, enamel formation appeared unaffected in Osr2-IresCre; Smad4(fl/fl) mice, challenging the paradigm that the initiation of enamel development depends on normal dentin formation. At the molecular level, loss of Smad4 results in downregulation of the WNT pathway inhibitors Dkk1 and Sfrp1 and in the upregulation of canonical WNT signaling, including increased beta-catenin activity. More importantly, inhibition of the upregulated canonical WNT pathway in Osr2-IresCre; Smad4(fl/fl) dental mesenchyme in vitro partially rescued the CNC cell fate change. Taken together, our study demonstrates that SMAD4 plays a crucial role in regulating the interplay between TGF beta/BMP and WNT signaling to ensure the proper CNC cell fate decision during organogenesis.