Wnt signaling in the induction of new tooth formation

尽管有关牙齿形态发生和分化的知识取得了进展，但人们对此知之甚少。 关于诱导牙齿形成的分子基础。我最近的研究表明，在上皮细胞上 APE的缺失或Wnt/p-catenin信号的激活，成人口腔组织，尤其是年轻的成人组织， 保留了成牙潜能，仍然可以形成新的牙齿，表明APE和Wnt/(3-catenin)是关键 牙齿诱导中的调控基因。此外，我还发现，猿类诱导多生牙 Wnt/(3-catenin)信号通路的激活导致了细胞功能的缺失。一旦启动，这些项目的发展 新的牙齿会自动进入细胞分化和生根阶段。我的长期目标是 阐明调控牙齿形成的分子机制，从而为 体外牙齿工程学。这项建议的目标是使用mRNA和miRNA微阵列来鉴定 Wnt/p-catenin信号的下游靶基因，并进一步分析它们的作用并利用它们来 体外诱导成牙。在K99指导阶段，我成功地从 &gt；APC功能丧失(LOP)和P-连环蛋白功能获得(GOF)小鼠，并比较它们的基因表达 使用Illumina微阵列的配置文件。与我的假设一致，大多数基因都显示出同时的变化 这两个突变的小鼠，以及我之前研究中测试的所有基因都显示出显著的变化 突变的牙胚与它们的对照后代进行比较。在Roo独立阶段。目标1，我会 继续与生物统计学家合作，进一步过滤和分析微阵列数据，以确定 牙齿形成过程中Wnt/(3-catenin)信号转导下游靶基因的研究在《目标2》中，我将重点介绍 使用体外和体内方法分析候选调控基因在牙齿启动中的作用。在……里面 目的3.建立一个体外培养系统来概括Wnt的非细胞自主效应 信号，并将进一步操纵关键的调控基因，在体外诱导牙齿。这些研究，如果 成功，将提供对牙齿和其他器官发育的基本见解，还可能 在临床上协助牙齿工程。

Despite advances in knowledge about tooth morphogenesis and differentiation, relatively little is known about the molecular basis of the induction of tooth formation. My recent studies show that upon epithelial deletion of Ape or activation of Wnt/p-catenin signaling, adult oral tissues, especially young adult tissues, retain odontogenic potential and can still form new teeth, indicating that Ape and Wnt/(3-catenin are key regulatory genes in tooth induction. Moreover, I have found that the induction of supernumerary teeth by Ape deficiency occurs through activation of Wnt/(3-catenin signaling. Once initiated, the development of these new teeth proceeds autonomously to stages of cell differentiation and root formation. My long-term goal is to elucidate the molecular mechanisms that regulate the initiation of tooth formation, thus paving the way for in vitro tooth engineering. The objective of this proposal is to use mRNA and miRNA microarrays to identify the downstream target genes of Wnt/p-catenin signaling, and further analyze their roles and utilize them to induce teeth in vitro. During the K99 mentored phase, I have successfully collected El4.5 tooth germs from >Apc loss of function (LOP) and P-catenin gain of function (GOF) mice, and compared their gene expression profiles using illumina microarray. Consistent with my hypothesis, most genes show concurrent changes in these two mutant mice, and all the genes tested in my previous studies exhibit significant changes in the mutant tooth germs compared to their control littermates. During the ROO independent phase. Aim 1, I will continue working with Biostatisticians to further filter and analyze the microarray data in order to identify the downstream target genes of Wnt/ (3-catenin signaling during tooth initiation. In Aim 2, I will focus on analyzing the role of candidate regulatory genes in tooth initiation using in vitro and in vivo approaches. In Aim 3, I will establish an in vitro culture system to recapitulate the non-cell autonomous effect of Wnt signaling, and will ifurther manipulate the key regulatory genes to induce teeth in vitro. These studies, if successful, will provide fundamental insights into the development of teeth and other organs, and may also assist in tooth engineering in the clinic.