Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, IA 52242, USA.
Development. 2013 Aug;140(16):3348-59. doi: 10.1242/dev.089193. Epub 2013 Jul 17.
The mouse incisor is a remarkable tooth that grows throughout the animal's lifetime. This continuous renewal is fueled by adult epithelial stem cells that give rise to ameloblasts, which generate enamel, and little is known about the function of microRNAs in this process. Here, we describe the role of a novel Pitx2:miR-200c/141:noggin regulatory pathway in dental epithelial cell differentiation. miR-200c repressed noggin, an antagonist of Bmp signaling. Pitx2 expression caused an upregulation of miR-200c and chromatin immunoprecipitation assays revealed endogenous Pitx2 binding to the miR-200c/141 promoter. A positive-feedback loop was discovered between miR-200c and Bmp signaling. miR-200c/141 induced expression of E-cadherin and the dental epithelial cell differentiation marker amelogenin. In addition, miR-203 expression was activated by endogenous Pitx2 and targeted the Bmp antagonist Bmper to further regulate Bmp signaling. miR-200c/141 knockout mice showed defects in enamel formation, with decreased E-cadherin and amelogenin expression and increased noggin expression. Our in vivo and in vitro studies reveal a multistep transcriptional program involving the Pitx2:miR-200c/141:noggin regulatory pathway that is important in epithelial cell differentiation and tooth development.
老鼠的门牙是一种非凡的牙齿，在动物的一生中不断生长。这种持续的更新是由成年上皮干细胞驱动的，这些干细胞产生成釉细胞，产生釉质，而关于 microRNAs 在这个过程中的功能知之甚少。在这里，我们描述了一个新的 Pitx2:miR-200c/141:noggin 调节途径在牙齿上皮细胞分化中的作用。miR-200c 抑制 noggin，一种 Bmp 信号的拮抗剂。Pitx2 的表达导致 miR-200c 的上调，并且染色质免疫沉淀测定显示内源性 Pitx2 与 miR-200c/141 启动子结合。发现 miR-200c 和 Bmp 信号之间存在正反馈环。miR-200c/141 诱导 E-钙黏蛋白和牙上皮细胞分化标志物釉原蛋白的表达。此外，内源性 Pitx2 激活了 miR-203 的表达，并靶向 Bmp 拮抗剂 Bmper 以进一步调节 Bmp 信号。miR-200c/141 敲除小鼠表现出釉质形成缺陷，E-钙黏蛋白和釉原蛋白表达减少，noggin 表达增加。我们的体内和体外研究揭示了一个涉及 Pitx2:miR-200c/141:noggin 调节途径的多步骤转录程序，该程序在上皮细胞分化和牙齿发育中非常重要。
