Roles of Bmp4 during tooth morphogenesis and sequential tooth formation
Roles of Bmp4 during tooth morphogenesis and sequential tooth formation
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DOI：
10.1242/dev.081927
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发表时间：
2013-01-15
期刊：
影响因子：
4.6
通讯作者：
Jiang, Rulang
中科院分区：
文献类型：
--
作者：
Jia, Shihai;Zhou, Jing;Jiang, Rulang
先前的研究表明，Bmp4是一个关键的msx1依赖的间充质牙源性信号，通过芽到帽的转变驱动牙齿形态发生。尽管在Msx1（-/-）小鼠中，所有牙齿细菌都在芽期被阻止，但我们发现，通过神经嵴特异性基因Bmp4失活，牙齿间质中功能性Bmp4 mrna的消耗（f/f）；Wnt1Cre小鼠，导致下颌磨牙发育停滞在萌芽期，但允许上颌磨牙和门牙发育成矿化牙。我们发现，编码锌指蛋白的Osr2的表达在Bmp4的磨牙间质中显著上调（f/f），该蛋白可拮抗msx1介导的牙源性间质激活；Wnt1Cre胚胎。Msx1杂合性增强了上颌磨牙发育缺陷，而Osr2杂合性部分挽救了Bmp4中下颌第一磨牙的形态发生（f/f）；Wnt1Cre老鼠。此外，与Msx1(-/-)Osr2（-/-）小鼠完全没有多余的牙齿形成相反，Osr2(-/-)Bmp4(f/f)；Wnt1Cre复合突变小鼠表现出多余牙齿细菌的形成和随后的抑制，这与牙齿间质中Msx1表达的下调有关。此外，我们发现Wnt抑制剂Dkk2和Wif1在野生型胚胎的下颌磨牙间质中的表达量远高于上颌磨牙间质，并且Dkk2在Bmp4的磨牙间质中的表达量显著上调（f/f）；Wnt1Cre胚胎，与Bmp4中上颌和下颌磨牙表型的显著差异相关（f/f）；Wnt1Cre老鼠。综上所述，这些数据表明Bmp4信号可以抑制牙齿间质中的发育抑制剂，包括Dkk2和Osr2，并与Msx1协同激活间质成牙潜能，促进牙齿形态发生和顺序牙齿形成。
Previous studies have suggested that Bmp4 is a key Msx1-dependent mesenchymal odontogenic signal for driving tooth morphogenesis through the bud-to-cap transition. Whereas all tooth germs were arrested at the bud stage in Msx1(-/-)mice, we show that depleting functional Bmp4 mRNAs in the tooth mesenchyme, through neural crest-specific gene inactivation in Bmp4(f/f); Wnt1Cre mice, caused mandibular molar developmental arrest at the bud stage but allowed maxillary molars and incisors to develop to mineralized teeth. We found that expression of Osr2, which encodes a zinc finger protein that antagonizes Msx1-mediated activation of odontogenic mesenchyme, was significantly upregulated in the molar tooth mesenchyme in Bmp4(f/f); Wnt1Cre embryos. Msx1 heterozygosity enhanced maxillary molar developmental defects whereas Osr2 heterozygosity partially rescued mandibular first molar morphogenesis in Bmp4(f/f); Wnt1Cre mice. Moreover, in contrast to complete lack of supernumerary tooth initiation in Msx1(-/-)Osr2(-/-)mice, Osr2(-/-)Bmp4(f/f); Wnt1Cre compound mutant mice exhibited formation and subsequent arrest of supernumerary tooth germs that correlated with downregulation of Msx1 expression in the tooth mesenchyme. In addition, we found that the Wnt inhibitors Dkk2 and Wif1 were much more abundantly expressed in the mandibular than maxillary molar mesenchyme in wild-type embryos and that Dkk2 expression was significantly upregulated in the molar mesenchyme in Bmp4(f/f); Wnt1Cre embryos, which correlated with the dramatic differences in maxillary and mandibular molar phenotypes in Bmp4(f/f); Wnt1Cre mice. Together, these data indicate that Bmp4 signaling suppresses tooth developmental inhibitors in the tooth mesenchyme, including Dkk2 and Osr2, and synergizes with Msx1 to activate mesenchymal odontogenic potential for tooth morphogenesis and sequential tooth formation.