Wnt signaling in the induction of new tooth formation

尽管牙齿形态发生和分化的知识有了很大的进步， 牙齿形成的分子基础我最近的研究表明， Ape的缺失或Wnt/β-连环蛋白信号传导的激活，成年口腔组织，特别是年轻的成年组织， 保持牙形成潜力，仍然可以形成新的牙齿，表明Ape和Wnt/β-catenin是关键 牙齿诱导中的调控基因。此外，我还发现，猿的多生牙齿的诱导， 缺陷通过Wnt/β-连环蛋白信号传导的激活而发生。一旦启动，这些发展 新的牙齿自主地进入细胞分化和牙根形成的阶段。我的长期目标是 阐明调节牙齿形成的分子机制，从而为研究 离体牙工程本提案的目的是使用mRNA和miRNA微阵列来鉴定 Wnt/β-catenin信号转导的下游靶基因，并进一步分析它们的作用， 体外诱导出牙齿。在K99指导阶段，我成功地收集了来自 >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微阵列的特征。与我的假设相一致，大多数基因显示出同时发生的变化， 这两个突变小鼠，以及我以前研究中测试的所有基因，都表现出显著的变化， 突变的牙胚与对照组相比。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 Wnt/β-catenin信号转导的下游靶基因。在目标2中，我将重点关注 使用体外和体内方法分析候选调控基因在牙齿发生中的作用。在 目的3：建立体外培养体系，重现Wnt的非细胞自主效应 信号通路的调控，并将进一步操纵关键调控基因，在体外诱导牙齿。这些研究，如果 成功的话，将为牙齿和其他器官的发育提供基本的见解，还可能 在诊所协助牙齿工程。

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.