牙齿发育异常特别是先天缺牙，是临床上最为常见的发育性疾病。牙齿发育是由许多基因、转录因子和信号传导分子参与的，遗传因素是造成牙齿发育异常的重要方面。了解牙齿发育过程的关键，就是要深入研究控制牙源性上皮和间充质细胞增殖、分化的信号通路，以及信号通路之间的相互作用。课题组的前期实验证实EDA和WNT10A的是先天缺牙的主要致病基因，并发现有患者同时存在上述两个基因的突变。研究显示在牙齿发育过程中EDA和WNT所介导的信号通路都发挥了重要的作用，但它们的交互作用尚不清楚。因此本项目拟利用人牙髓干细胞进行体外实验，研究EDA和WNT信号通路的相互作用，以及下游信号通路的变化。同时，我们将构建Wnt10a基因敲除小鼠模型，并且利用Eda缺陷的Tabby小鼠模型，通过体内功能实验阐明牙齿发育过程中EDA和WNT信号通路的交互作用及其重要的生物学功能。为研究牙齿发育异常的病因机制提供新的理论依据。

Tooth anomalies, especially hypodontia, are the most common developmental disorder seen in clinic. Tooth development is a complex procedure that involves many genes, transcription factors and signaling molecules. Genetic factors play an important role during the tooth development. To understand the mechanism of tooth development, we need to study signaling pathways that control the proliferation and differentiation of dental epithelial and mesenchymal cells, and the interaction between these signal factors. Our preliminary study suggests that EDA and WNT10A are two of the most important disease associate genes of hypodontia. We also found that some patients carry mutations in both of the two genes. EDA and WNT-mediated signaling pathways have been shown to play key roles during tooth initiation and morphogenesis. However, the interaction between these two pathways is still unknown. In this proposal, we will use human dental pulp stem cells to study the interaction of EDA and WNT signaling pathway and their downstream signals in vitro. We will also establish Wnt10a gene knockout mouse. Together with Eda deficient Tabby mice, we will perform in vivo functional analysis to reveal the interaction of the EDA and the WNT signaling pathway during tooth development and genes related to these networks. This study will unveil novel mechanism of tooth development and dental abnomlies.