The Role of Wnt Signaling in Early Tooth Development

 描述（由申请人提供）：Wnt信号通路在胚胎发育和成体组织稳态中起着重要作用。Wnt信号传导可以分为经典和非经典，这取决于在Wnt响应细胞中哪些效应器中继信号。经典的Wnt信号通路由β-连环蛋白介导，而非经典的通路是β-连环蛋白不依赖的。发育生物学中一个重要的未解决的问题是典型的Wnt信号如何调节牙齿发育的早期阶段（牙发生）。揭示Wnt信号在牙齿发育中的作用的主要限制之一是缺乏牙齿祖细胞的特异性标记物。先前的研究利用Wnt信号在口腔上皮和间充质组织中的一般激活和消融来研究它如何调节牙发生。然而，这种广泛的靶向使我们对Wnt信号传导与牙齿发生之间关系的理解变得复杂。我们最近发现Fgf 8在E11.5的瞬时表达标志着牙上皮祖细胞（DEPCs）。基于这一发现，我在DEPC中特异性激活了Wnt信号，与正常发生的上皮内陷到底层牙齿间充质中相反，我发现上皮外翻到口腔中。这一观察使我假设经典的Wnt信号调节DEPC沿着上下轴的位置。通过这个项目，我将进一步探索典型的Wnt信号在牙齿发育过程中的作用，通过评估DEPC的Wnt-反应性，并采取获得和丧失功能的方法来评估Wnt信号在牙齿发育中从分子到器官水平的调节作用。了解牙齿上皮内陷的机制，以及DEPC的迁移模式和牙齿形态之间的关系，对于理解牙齿发育的机制至关重要。因此，这项研究可以为基础牙齿生物学以及再生医学（如治疗性牙齿组织工程）提供重要的见解。

 DESCRIPTION (provided by applicant): The Wnt signaling pathway plays a central role in embryonic development and adult tissue homeostasis. Wnt signaling can be categorized into canonical and non-canonical, depending on which effectors relay signals in Wnt-responsive cells. The canonical Wnt signaling pathway is mediated by ß-catenin, whereas non-canonical pathways are ß-catenin-independent. An important unsolved question in developmental biology is how canonical Wnt signaling regulates early stages of tooth development (odontogenesis). One of the major limitations in uncovering the role of Wnt signaling in tooth development has been a lack of specific markers for dental progenitor cells. Previous studies utilized general activation and ablation of Wnt signaling in oral epithelial and mesenchymal tissues to study how it regulates odontogenesis. However, this broad targeting complicates our understanding of the relationship between Wnt signaling and odontogenesis. We have recently discovered that transient expression of Fgf8 at E11.5 marks dental epithelial progenitor cells (DEPCs). Building on this finding, I activated Wnt signaling specifically in DEPCs, and in contrast to the normally occurring invagination of the epithelium into the underlying dental mesenchyme, I found that the epithelium evaginated into the oral cavity. This observation led me to hypothesize that canonical Wnt signaling regulates the position of DEPCs along the superior-inferior axis. Through this project, I will further explore the role of canonical Wnt signaling during tooth development by assessing the Wnt- responsiveness of DEPCs, and by taking gain- and loss-of-function approaches to evaluate the regulatory role of Wnt signaling in tooth development from the molecular to the organ level. Understanding the mechanism underlying invagination of dental epithelium, as well as the relationship between the migration pattern of DEPCs and the resulting dental morphology, is crucial for understanding the mechanics of tooth development. Thus, this study can provide significant insight into basic tooth biology as well as for regenerative medicine, such as therapeutic dental tissue engineering.