Nonclassical β-catenin signaling in odontogenesis

摘要 本研究的主要目的是阐明牙齿发育的调控机制。 由非经典的β-连环蛋白信号介导。牙齿发育不全是最常见的先天性牙病 畸形，特征是缺少一颗或多颗恒牙，包括缺牙症、少齿牙、 和哈波顿西亚。人类对非综合征性牙齿发育不全的遗传学研究揭示了大约16种 其中6个致病基因参与了Wnt通路，表明其在疾病中的意义 发病机制。缺失的牙齿目前通过牙科植入物、牙齿移植或修复来治疗。 修理。然而，它们不是永久性的治疗方法，而且还与相当大的并发症有关。 对于下一代疗法，中断牙齿形成/维护的新再生方法或 开发一种自体牙齿替换是非常有吸引力的概念。因此，推进我们的 了解牙齿发育并阐明牙齿相互作用的机制 上皮细胞和间质细胞。由β-连环蛋白介导的规范Wnt信号转导已被证实 在早期牙齿发育中起着至关重要的作用。小鼠遗传学研究证明了Wnt的重要性 信号在牙科医学的各个方面，例如牙齿发育、牙髓、釉质、牙齿发育、 和成釉作用。降解缺陷形式的β-连环蛋白的表达可导致持续的牙齿生成 和多余牙齿的发育，进一步表明牙齿更新可以通过增加 成牙潜力的内在水平。β-连环蛋白作为这一内在潜力的主调节器 促进牙齿的形成。然而，β-连环蛋白是一种除具有其他功能外还具有其他功能的多面体蛋白 作为传递规范的Wnt信号的主调节器。我们新基因的初步研究 模型驳斥了现有的知识，并暗示了非经典β-连锁素的要求 牙齿发育。首先，我们将鉴定新的β-连环蛋白突变小鼠，以严格评估其双重功能。 β-连环蛋白在成牙本质细胞和成釉细胞分化中的作用 第二，我们将通过单细胞转录鉴定作用于β-连环蛋白下游的主要调节子。 破译与非经典信号级联相关的遗传调控网络的方法。这个 目的本研究对人类健康和牙科再生医学具有重要意义。澄清 牙齿发育调控的潜在机制为下一代提供了重要的见解 牙齿修复的治疗。

Abstract The primary objective of this application is to elucidate the regulatory mechanisms underlying odontogenesis mediated by nonclassical β-catenin signaling. Tooth agenesis is the most common congenital dental abnormality, characterized by the absence of one or more permanent teeth including Anodontia, Oligodontia, and Hypodontia. Human genetic studies of nonsyndromic tooth agenesis have revealed approximately 16 causative genes of which 6 of them are involved in the Wnt pathway indicating its significance in disease pathogenesis. Missing teeth are currently treated by dental implants, tooth transplants, or prosthodontic repairs. However, they are not permanent treatments and also are associated with considerable complications. For next-generation therapies, new regenerative approaches to interrupt tooth formation/maintenance or develop an autologous tooth replacement are highly attractive concepts. Therefore, it is critical to advance our knowledge of odontogenesis and elucidate the mechanisms underlying reciprocal interactions of dental epithelium and mesenchyme. Canonical Wnt signaling mediated by β-catenin has been well established to play an essential role in early odontogenesis. Mouse genetic studies have demonstrated the importance of Wnt signaling in various aspects of dental medicine, e.g. tooth development, dental pulp, enamel, odontogenesis, and amelogenesis. Expression of a degradation-deficient form of β-catenin causes continuous tooth generation and development of supernumerary teeth, further suggesting that tooth renewal can be unlocked by increasing the intrinsic level of odontogenic potential. β-catenin acts as a master regulator of this intrinsic potential to promote tooth formation. However, β-catenin is a multifaced protein that possesses other functions in addition to acting as a master regulator for transducing canonical Wnt signaling. Preliminary studies of our new genetic models argue against current knowledge and implicate the requirement of nonclassical β-catenin in odontogenesis. First, we will characterize new β-catenin mutant mice to rigorously assess the dual function of β-catenin in the development of odontogenic ability, and differentiation of odontoblasts and ameloblasts. Second, we will identify the master regulators acting downstream of β-catenin by a single-cell transcriptomic approach to decipher the genetic regulatory network associated with the nonclassical signaling cascade. The objective of this study has great significance in human health and regenerative dental medicine. Elucidating the mechanism underlying the regulation of odontogenesis promises important insights into next-generation therapy for dental restoration.