Activated Epithelial FGF8 Signaling Induces Fused Supernumerary Incisors
Activated Epithelial FGF8 Signaling Induces Fused Supernumerary Incisors
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激活的上皮 FGF8 信号传导诱导多生切牙融合
DOI：
10.1177/00220345211046590
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Y Zhang
中科院分区：
文献类型：
--
作者：
Y Chen;Z wang;C Lin;Y Chen;X Hu;Y Zhang
FGF 8在E12.5芽期之前特异性地表达于牙上皮中，是牙发生过程中的关键参与者，负责牙齿发育的启动。在这里，为了研究持续的FGF 8信号传导对牙齿发育的影响，我们通过产生K14-Cre; R26 R-Fg 8小鼠在芽期后强制激活牙上皮中的FGF 8信号传导。我们发现，一个独特的类型的融合多余的门牙形成，虽然形态相似的功能，第二型牙套在人类。进一步的分析显示，异位激活的上皮FGF 8改变了切牙舌外釉上皮的细胞命运，通过激活几个关键的牙齿基因，包括Pitx 2、Sox 2、Lef-1、p38和Erk 1/2，赋予其牙形成潜力，并诱导舌侧与原始牙冠平行的额外切牙牙冠的重新形成，导致形成额外的门牙牙冠，并最终与原来的门牙融合。同时，过量的上皮FGF 8信号转导显著下调间充质Bmp 4的表达，导致严重受损的釉质矿化。根据额外门牙的位置，我们认为它们很可能是被抢救的替换牙齿。我们的研究结果进一步证明了FGF 8信号在牙齿发生和牙上皮干细胞祖细胞的建立中的重要作用。
FGF8, which is specifically expressed in the dental epithelium prior to the E12.5 bud stage, is a key player during odontogenesis, being responsible for the initiation of tooth development. Here, to investigate the impact of persistent FGF8 signaling on tooth development, we forcibly activated FGF8 signaling in the dental epithelium after the bud stage by generating K14-Cre;R26R-Fg8 mice. We found that a unique type of fused supernumerary incisors is formed, although morphologically resembling the features of type II dens invaginatus in humans. Further analysis revealed that ectopically activated epithelial FGF8 alters the cell fate of the incisor lingual outer enamel epithelium, endowing it with odontogenic potential by the activation of several key tooth genes, including Pitx2, Sox2, Lef-1, p38, and Erk1/2, and induces de novo formation of an extra incisor crown lingually in parallel to the original one, leading to the formation of an extra incisor crown and fused with the original incisor eventually. Meanwhile, the overdosed epithelial FGF8 signaling dramatically downregulates the expression of mesenchymal Bmp4, leading to severely impaired enamel mineralization. Based on the location of the extra incisors, we propose that they are likely to be rescued replacement teeth. Our results further demonstrate the essential role of FGF8 signaling for tooth initiation and the establishment of progenitor cells of dental epithelial stem cells during development.
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