Nonclassical β-catenin signaling in odontogenesis

摘要 本申请的主要目的是阐明牙齿发生的调控机制 由非经典β-catenin信号传导介导。牙齿发育不全是最常见的先天性牙齿 异常，其特征在于缺少一个或多个恒牙，包括无牙，少牙， 和Hypodontia。对非综合征性牙齿发育不全的人类遗传学研究显示， 致病基因，其中6个参与Wnt途径，表明其在疾病中的重要性 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。 维修.然而，它们不是永久性的治疗，并且还与相当多的并发症有关。 对于下一代治疗，新的再生方法可以中断牙齿形成/维护， 开发自体牙齿替代物是非常有吸引力的概念。因此，至关重要的是， 了解牙齿发生，阐明牙齿相互作用的机制， 上皮和间充质。β-连环蛋白介导的经典Wnt信号传导已经被很好地建立， 在早期牙形成中起重要作用。小鼠遗传学研究表明Wnt的重要性 在牙科医学的各个方面，例如牙齿发育、牙髓、釉质、牙齿发生， 和釉质形成。β-连环蛋白降解缺陷型的表达导致牙齿的连续生成 和多生牙的发展，进一步表明牙齿更新可以通过增加 牙源性潜能的内在水平。β-连环蛋白作为这种内在潜力的主要调节因子， 促进牙齿形成。然而，β-catenin是一种多面蛋白，除此之外还具有其他功能 作为一个主调节器转导经典Wnt信号。我们新基因的初步研究 模型与现有的知识相矛盾，并暗示了非经典β-连环蛋白的需求， 牙发生首先，我们将描述新的β-连环蛋白突变小鼠，以严格评估β-连环蛋白的双重功能。 β-catenin在成牙本质细胞和成釉细胞成牙本质能力发育及分化中的作用 其次，我们将通过单细胞转录组学鉴定β-catenin下游的主要调节因子。 方法来破译与非经典信号级联相关的遗传调控网络。的 目的本研究对人类健康和口腔再生医学具有重要意义。阐明 牙齿发生调控的潜在机制有望为下一代牙齿的发育提供重要的见解。 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.