PDF(Pubmed)
Abstract：
Putatively, tooth agenesis was attributed to the initiation failure of tooth germs, though little is known about the histological and molecular alterations. To address if constitutively active FGF signaling is associated with tooth agenesis, we activated Fgf8 in dental mesenchyme with Osr-cre knock-in allele in mice (Osr2-creKI; Rosa26R-Fgf8) and found incisor agenesis and molar microdontia. The cell survival assay showed tremendous apoptosis in both the Osr2-creKI; Rosa26R-Fgf8 incisor epithelium and mesenchyme, which initiated incisor regression from cap stage. In situ hybridization displayed vanished Shh transcription, and immunostaining exhibited reduced Runx2 expression and enlarged mesenchymal Lef1 domain in Osr2-creKI; Rosa26R-Fgf8 incisors, both of which were suggested to enhance apoptosis. In contrast, Osr2-creKI; Rosa26R-Fgf8 molar germs displayed mildly suppressed Shh transcription, and the increased expression of Ectodin, Runx2 and Lef1. Although mildly smaller than WT controls prenatally, the Osr2-creKI; Rosa26R-Fgf8 molar germs produced a miniature tooth with impaired mineralization after a 6-week sub-renal culture. Intriguingly, the implanted Osr2-creKI; Rosa26R-Fgf8 molar germs exhibited delayed odontoblast differentiation and accelerated ameloblast maturation. Collectively, the ectopically activated Fgf8 in dental mesenchyme caused incisor agenesis by triggering incisor regression and postnatal molar microdontia. Our findings reported tooth agenesis resulting from the regression from the early bell stage and implicated a correlation between tooth agenesis and microdontia.
摘要：
推定,牙齿发育不全归因于牙胚的萌生失败，尽管对组织学和分子改变知之甚少。为了解决组成型活性FGF信号是否与牙齿发育不全有关，我们在小鼠中使用Osr-cre敲入等位基因（Osr2-creKI；Rosa26R-Fgf8）激活了牙齿间充质中的Fgf8，并发现了切牙发育不全和磨牙牙髓。细胞存活试验显示，Osr2-creKI;Rosa26R-Fgf8切牙上皮和间充质细胞凋亡巨大，从帽阶段开始门牙回归。原位杂交显示Shh转录消失，和免疫染色显示Osr2-creKI中Runx2表达减少和间充质Lef1结构域扩大;Rosa26R-Fgf8切牙,两者都被认为可以增强细胞凋亡。相比之下,Osr2-creKI；Rosa26R-Fgf8磨牙病菌表现出轻度抑制的Shh转录，和促凋亡素的表达增加，Runx2和Lef1。尽管在产前比WT控制稍小，Osr2-creKI;Rosa26R-Fgf8磨牙细菌在6周的肾下培养后产生了一颗矿化受损的微型牙齿。有趣的是，植入的Osr2-creKI；Rosa26R-Fgf8磨牙细菌表现出成牙本质细胞分化延迟和成釉细胞成熟加速。总的来说，牙间充质中异位激活的Fgf8通过触发门牙消退和出生后磨牙小牙体而引起门牙发育不全。我们的发现报告了牙齿发育不全是由于从钟形早期开始消退而引起的，并暗示了牙齿发育不全与牙体之间的相关性。
