Program in Craniofacial Biology and Department of Orofacial Sciences, UCSF School of Dentistry, University of California, San Francisco, San Francisco, CA, USA.
Université Paris Descartes, Sorbonne Paris Cite, UMR S872, Paris, France.
J Bone Miner Res. 2017 Nov;32(11):2219-2231. doi: 10.1002/jbmr.3202. Epub 2017 Jul 31.
Rodents are characterized by continuously renewing incisors whose growth is fueled by epithelial and mesenchymal stem cells housed in the proximal compartments of the tooth. The epithelial stem cells reside in structures known as the labial (toward the lip) and lingual (toward the tongue) cervical loops (laCL and liCL, respectively). An important feature of the rodent incisor is that enamel, the outer, highly mineralized layer, is asymmetrically distributed, because it is normally generated by the laCL but not the liCL. Here, we show that epithelial-specific deletion of the transcription factor Islet1 (Isl1) is sufficient to drive formation of ectopic enamel by the liCL stem cells, and also that it leads to production of altered enamel on the labial surface. Molecular analyses of developing and adult incisors revealed that epithelial deletion of Isl1 affected multiple, major pathways: Bmp (bone morphogenetic protein), Hh (hedgehog), Fgf (fibroblast growth factor), and Notch signaling were upregulated and associated with liCL-generated ectopic enamel; on the labial side, upregulation of Bmp and Fgf signaling, and downregulation of Shh were associated with premature enamel formation. Transcriptome profiling studies identified a suite of differentially regulated genes in developing Isl1 mutant incisors. Our studies demonstrate that ISL1 plays a central role in proper patterning of stem cell-derived enamel in the incisor and indicate that this factor is an important upstream regulator of signaling pathways during tooth development and renewal. © 2017 American Society for Bone and Mineral Research.
啮齿动物的特征是不断更新的门齿，其生长由位于牙齿近端隔室的上皮和间充质干细胞驱动。上皮干细胞位于称为唇（朝向嘴唇）和舌（朝向舌头）颈环（laCL 和 liCL）的结构中。啮齿动物门齿的一个重要特征是，外覆的高度矿化的釉质层是不对称分布的，因为它通常由 laCL 产生，但不由 liCL 产生。在这里，我们表明，上皮特异性缺失转录因子 Islet1（Isl1）足以驱动 liCL 干细胞形成异位釉质，并且还导致唇侧表面产生改变的釉质。对发育中和成年门齿的分子分析表明，上皮细胞中 Isl1 的缺失影响了多个主要途径：Bmp（骨形态发生蛋白）、Hh（ hedgehog）、Fgf（成纤维细胞生长因子）和 Notch 信号被上调，并与 liCL 产生的异位釉质有关；在唇侧，Bmp 和 Fgf 信号的上调以及 Shh 的下调与早期釉质形成有关。转录组分析研究确定了在发育中的 Isl1 突变体门齿中有一套差异调节的基因。我们的研究表明，ISL1 在门齿中干细胞衍生釉质的正确模式形成中起着核心作用，并表明该因子是牙齿发育和更新过程中信号通路的重要上游调节剂。 © 2017 美国骨骼矿物质研究协会。
