WNT signals in developing and postnatal teeth

发育中和产后牙齿中的 WNT 信号

• 批准号: 7274157
• 负责人: Sarah E. Millar
• 金额: $ 33.81万
• 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/7274157
• 关键词: Adult; Ameloblasts; Biological Assay; Biological Models; Candidate Disease Gene; Cell Nucleus; Cells; Cyclin Gene; Data; Defect; Dental; Dental Enamel; Dental caries; Development; Embryo; Epithelial; Epithelial Cells; Epithelium; Gardner' s Syndrome; Gene Targeting; Growth; In Vitro; Inborn Genetic Diseases; Incisor; Individual; Localized; Maintenance; Mandible; Mediating; Mesenchyme; Morphogenesis; Mus; Natural regeneration; Odontogenic Tumors; Odontoma; Pathway interactions; Patients; Play; Population; Primordium; Proteins; Reporter; Rodent; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Staging; Stem cells; Structure; Supernumerary Tooth; System; Testing; Time; Tooth Germ; Tooth structure; Transgenes; Transgenic Mice; Transgenic Organisms; WNT Signaling Pathway; beta catenin; cyclin D2; in vivo; loss of function mutation; novel therapeutics; paracrine; postnatal; precursor cell; receptor; research study; stem cell fate

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.

产品说明：上皮细胞之间以及上皮和间充质之间的信号传导是牙齿形态发生和出生后啮齿动物切牙连续生长所必需的，这是研究牙齿上皮干细胞的模型系统。因此，识别负责的细胞间信号分子及其靶点对于理解牙齿发育的遗传性疾病至关重要，并可能最终揭示治疗龋齿和再生成人牙齿的新治疗策略。抑制旁分泌WNT/β-catenin信号传导导致牙齿发育早期停滞;相反，经典WNT/β-catenin通路的激活导致Gardner综合征患者的牙瘤和多生牙，转基因小鼠异位牙芽样结构的形成，以及出生后小鼠切牙成釉细胞的丧失，表明WNT信号传导在牙齿发育中起着多种作用。Eda和Pitx 2基因是WNT/β-连环蛋白信号传导的候选直接靶点，其在牙齿上皮中表达并且是牙齿发育所需的。我们认为，特定的典型WNT蛋白促进牙齿的命运在胚胎中，并调节增殖的胚胎牙齿原基和成釉细胞前体细胞在出生后的门牙，这些功能介导的部分通过激活的EDA和Pitx 2。为了验证这一假设，我们提出了三个具体目标。在具体目标1中，我们将确定在胚胎牙齿发育过程中和出生后门牙中对WNT/β-连环蛋白信号做出反应的细胞群。在具体目标2中，我们将通过以下方式剖析牙齿发育中Eda、Pitx 2和WNT之间的关系：（i）确定Eda和Pitx 2在牙齿发育的不同阶段是否需要WNT/β-连环蛋白信号传导来表达;（ii）测试Eda或Pitx 2靶基因细胞周期蛋白D2的强制表达是否可以部分挽救WNT抑制的效果;和（iii）确定WNT诱导的牙齿发育促进是否需要Eda或Pitx 2功能。在特定目标3中，我们将鉴定能够促进牙齿发育的单个WNT蛋白，并将确定WNT/β-连环蛋白信号传导的激活是否足以诱导Eda和Pitx 2的表达，启动牙齿发育，诱导牙源性肿瘤，或调节切牙成釉细胞前体的活性。这些实验将有助于将WNT信号置于控制牙齿发育的调节因子网络中，并将测试WNT激活在牙齿或釉质再生策略中的潜在用途。