WNT signals in developing and postnatal teeth

发育中和产后牙齿中的 WNT 信号

• 批准号: 6870128
• 负责人: Sarah E. Millar
• 金额: $ 34.84万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-28 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6870128
• 关键词: ameloblasts; biological signal transduction; cadherins; cell cell interaction; cell differentiation; cell growth regulation; cell population study; cell proliferation; cyclins; dental development; embryo /fetus; embryonic stem cell; epithelium; gene expression; gene targeting; genetically modified animals; histology; laboratory mouse; mammalian embryology; mouth neoplasms; protein tyrosine kinase; regeneration; stem cells; tissue /cell culture; tooth

DESCRIPTION: Signaling between epithelial cells and between the epithelium and mesenchyme is required for tooth morphogenesis and for continuous growth of postnatal rodent incisor teeth, a model system for studying Dental epithelial stem cells. Identification of the responsible intercellular signaling molecules and their targets is therefore essential for understanding inherited disorders of tooth development, and may ultimately reveal novel therapeutic strategies for treatment of tooth decay and for regenerating teeth in adults. Inhibition of paracrine WNT/beta-catenin signaling causes an early arrest of tooth development; conversely activation of the canonical WNT/beta-catenin pathway causes odontomas and supernumerary teeth in Gardner s syndrome patients, formation of ectopic tooth bud-like structures in transgenic mice, and loss of ameloblasts from postnatal mouse incisor teeth, suggesting that WNT signaling plays multiple roles in tooth development. The Eda and Pitx2 genes are candidate direct targets of WNT/beta-catenin signaling that are expressed in Dental epithelium and required for tooth development. We posit that specific canonical WNT proteins promote tooth fate in the embryo and regulate the proliferation of embryonic Dental primordia and ameloblast precursor cells in postnatal incisor teeth, and that these functions are mediated in part through activation of Eda and Pitx2. To test this hypothesis we propose three Specific Aims. In Specific Aim 1 we will identify cell populations that respond to WNT/beta-catenin signals during embryonic tooth development and in postnatal incisor teeth. In Specific Aim 2 we will dissect the relationship between Eda, Pitx2 and WNT in tooth development by: (i) determining whether Eda and Pitx2 require WNT/beta-catenin signaling for their expression at different stages of tooth development; (ii) testing whether forced expression of Eda or the Pitx2 target gene cyclin D2 can partially rescue the effects of WNT inhibition; and (iii) determining whether Eda or Pitx2 function is required for WNT induced promotion of tooth development. In Specific Aim 3 we will identify individual WNT proteins that are capable of promoting tooth development, and will determine whether activation of WNT/beta-catenin signaling is sufficient to induce expression of Eda and Pitx2, initiate tooth development, induce odontogenic tumors, or regulate the activity of incisor tooth ameloblast precursors. These experiments will help to place WNT signals in the network of regulatory factors that control tooth development, and will test the potential use of WNT activation in strategies for tooth or enamel regeneration.

描述：上皮细胞之间以及上皮和间质之间的信号传导是牙齿形态发生和产后啮齿动物切牙牙齿的持续生长所必需的，这是一种用于研究牙齿上皮干细胞的模型系统。因此，鉴定负责任的细胞间信号分子及其靶标对于理解牙齿发育的遗传疾病至关重要，最终可能揭示了用于治疗牙齿衰减和再生成人牙齿的新型治疗策略。抑制旁分泌Wnt/β-catenin信号传导会引起牙齿发育的早期停滞；相反，Gardner S综合征患者的典范Wnt/β-catenin途径的激活会导致尾to和超生物牙齿，转基因小鼠中异位牙齿芽样结构的形成，以及产后小鼠牙齿的未整体牙齿的丧失，这表明Wnt信号在牙齿发育中发挥了多种作用。 EDA和PITX2基因是Wnt/beta-catenin信号传导的候选靶标，在牙齿上皮表达并进行牙齿发育所需。我们认为，特定的规范Wnt蛋白会在胚胎中促进牙齿命运，并调节产后牙齿牙齿中胚胎牙科原始牙齿和成纤维细胞前体细胞的增殖，并且这些功能部分通过EDA和PITX2激活而部分介导。为了检验这一假设，我们提出了三个具体目标。在特定目标1中，我们将确定在胚胎发育过程中和产后牙齿中对Wnt/β-catenin信号响应的细胞群体。在特定的目标2中，我们将通过以下方式在牙齿发育中剖析EDA，PITX2和Wnt之间的关系：（i）确定EDA和PITX2是否需要Wnt/beta-catenin信号在牙齿发育的不同阶段表达； （ii）测试EDA的强迫表达或PITX2靶基因Cyclin D2是否可以部分挽救Wnt抑制作用； （iii）确定Wnt诱导牙齿发育的促进是否需要EDA或PITX2功能。在特定目标3中，我们将确定能够促进牙齿发育的单个Wnt蛋白，并确定Wnt/β-catenin信号的激活是否足以诱导EDA和PITX2的表达，启动牙齿发育，诱导牙基因源性肿瘤，或者调节牙入牙齿肌细胞增生剂的活性。这些实验将有助于将WNT信号放置在控制牙齿发育的调节因素网络中，并将测试Wnt激活在牙齿或搪瓷再生策略中的潜在使用。