An atypical canonical bone morphogenetic protein (BMP) signaling pathway regulates msh homeobox 1 (Msx1) expression during odontogenesis
An atypical canonical bone morphogenetic protein (BMP) signaling pathway regulates msh homeobox 1 (Msx1) expression during odontogenesis
复制标题
非典型典型骨形态发生蛋白 (BMP) 信号通路在牙发生过程中调节 msh 同源盒 1 (Msx1) 表达
DOI：
10.1074/jbc.m114.600064
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发表时间：
2014
影响因子：
4.8
通讯作者：
Chen YiPing
中科院分区：
文献类型：
--
作者：
Yang Guobin;Yuan Guohua;Ye Wenduo;Cho Ken W. Y.;Chen YiPing
骨形态发生蛋白 (BMP) 信号传导在早期牙齿发育中起着至关重要的作用，BMP 信号传导破坏导致牙齿发育早期停滞就证明了这一点。尽管 Smad4 是 BMP 经典信号通路的核心介质，但牙齿间充质中的 Smad4 失活不会导致早期发育缺陷。在本研究中，我们研究了受体激活的Smads（R-Smads）和Smad4在调节牙源性基因Msx1在牙间充质中表达的机制。我们通过BRE-Gal转基因等位基因的激活失败和磷酸-(p)Smad1/5/8-Smad4复合物的缺失来评估，表明规范的BMP信号在早期发育的牙齿中不起作用。 pSmad1/5/8-Smad4 复合物的缺失似乎是牙科间充质中 Smad4 被 pSmad2/3 饱和的结果，因为 Smad2/3 的敲低或 Smad4 的过度表达导致 pSmad1/5/8-Smad4 复合物的形成并激活牙科间充质细胞中的经典 BMP 信号传导。我们发现，BMP 诱导的牙科间充质细胞中 Msx1 的表达需要 Smad1/5，而不是 Smad4。我们进一步提供的证据表明，在缺乏 Smad4 的情况下，BMP 仍然能够诱导 pSmad1/5/8 核转位，并直接与牙科间充质细胞中的 Msx1 启动子结合。我们的结果证明了早期牙发育过程中牙齿间充质中非典型典型 BMP 信号（Smad4 独立和 Smad1/5/8 依赖）通路的功能运作，这可能对其他器官的发育具有普遍意义。
Bone morphogenetic protein (BMP) signaling plays an essential role in early tooth development, evidenced by disruption of BMP signaling leading to an early arrested tooth development. Despite being a central mediator of BMP canonical signaling pathway, inactivation ofSmad4in dental mesenchyme does not result in early developmental defects. In the current study, we investigated the mechanism of receptor-activated Smads (R-Smads) and Smad4 in the regulation of the odontogenic geneMsx1expression in the dental mesenchyme. We showed that the canonical BMP signaling is not operating in the early developing tooth, as assessed by failed activation of theBRE-Galtransgenic allele and the absence of phospho-(p)Smad1/5/8-Smad4 complexes. The absence of pSmad1/5/8-Smad4 complex appeared to be the consequence of saturation of Smad4 by pSmad2/3 in the dental mesenchyme as knockdown of Smad2/3 or overexpression of Smad4 led to the formation of pSmad1/5/8-Smad4 complexes and activation of canonical BMP signaling in dental mesenchymal cells. We showed that Smad1/5 but not Smad4 are required for BMP-induced expression ofMsx1in dental mesenchymal cells. We further presented evidence that in the absence of Smad4, BMPs are still able to induce pSmad1/5/8 nuclear translocation and their binding to theMsx1promoter directly in dental mesenchymal cells. Our results demonstrate the functional operation of an atypical canonical BMP signaling (Smad4-independent and Smad1/5/8-dependent) pathway in the dental mesenchyme during early odontogenesis, which may have general implication in the development of other organs.