GENETIC ANALYSIS OF THE MECHANISMS THAT REGULATE TOOTH MORPHOGENESIS

牙齿形态发生调节机制的遗传学分析

• 批准号: 7659659
• 负责人: GAIL R. MARTIN
• 金额: $ 35.98万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659659
• 关键词: Adult; Affect; Alleles; Ameloblasts; Anterior; Cell Proliferation; Cells; Characteristics; Complex; Data; Dental; Dentition; Development; Embryo; Embryonic Development; Epithelial; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Gene Expression; Genes; Genetic; Genetic Crosses; Genetic screening method; Goals; Gophers; Growth; In Vitro; Incisor; Individual; Kinetics; Knowledge; Lead; Learning; Life; Ligands; Mediator of activation protein; Mesenchymal; Molecular; Morphogenesis; Mus; Mutation; Odontoblasts; Organ; Organ Culture Techniques; Organogenesis; Pathway interactions; Patients; Phenotype; Play; Primordium; Process; Proteins; Public Health; Receptor Protein-Tyrosine Kinases; Regulator Genes; Research Personnel; Role; Scientist; Signal Pathway; Signal Transduction; Stem cells; Supernumerary Tooth; Testing; Tooth Germ; Tooth structure; Wild Type Mouse; gene function; genetic analysis; insight; loss of function; loss of function mutation; mouse development; null mutation; postnatal; prevent; programs; receptor; research study; stem cell biology; stem cell fate; stem cell niche; teeth diastema

DESCRIPTION (provided by applicant): These studies are aimed at understanding the mechanisms that regulate tooth number and morphogenesis. We will take a genetic approach, using mice carrying mutations in Sprouty (Spry) genes, which encode proteins that antagonize signaling via Fibroblast Growth Factors (FGFs). The FGF signaling pathway plays a key role in orchestrating morphogenesis of the tooth as well as many other organs. Analyzing how alterations in FGF signaling perturb tooth development, when these alterations are caused by removing an antagonist of FGF signaling, will lead to new insights that could not be obtained by studying loss-of-function mutations in either individual FGF ligands or their receptors. Our specific goals are: 1) study mice lacking either Spry2 or Spry4 function, in which tooth buds anterior to the first molar develop into supernumerary teeth. In wild-type mice, these buds regress to yield a toothless diastema region. By analyzing gene expression, performing experiments in tooth organ cultures, and by analyzing the progeny of complex genetic crosses, we will determine how loss of Sprouty gene function enables diastema tooth buds to persist and develop into a tooth rather than regress. Our studies will lead to a better understanding of the normal mechanisms by which diastema buds are prevented from forming teeth in the mouse and by which molar development is regulated. 2) pursue our observation that inactivation of multiple Sprouty alleles has profound effects on incisor development, including development of duplicate incisors. We propose to study the normal morphogenesis of early incisors, and then examine how this process is disturbed by deletion of Sprouty gene function. 3) determine why remarkable tusk-like incisors develop in mice that are heterozygous for Spry2 and null for Spry4. We will focus on the role of FGF signaling in controlling fate decisions during embryogenesis and in regulating progenitor cell proliferation and differentiation in the adult. Results from these studies will enhance our understanding of the signaling pathways that control epithelial-mesenchymal interactions during organogenesis and will contribute to knowledge about the stem-cell niche in the adult mouse incisor. Public health implications: Through our studies we will learn more about how teeth normally develop and how this development goes awry in patients with dental abnormalities. We will also study the mechanisms that control stem cells in adult teeth, which may help to lay the groundwork for efforts to build new teeth.

描述（由申请人提供）：这些研究旨在了解调节牙齿数和形态发生的机制。我们将采用一种遗传方法，使用发芽（SPRY）基因中的小鼠携带突变，该基因编码通过成纤维细胞生长因子（FGFS）拮抗信号传导的蛋白质。 FGF信号通路在编排牙齿的形态发生以及许多其他器官中起着关键作用。分析FGF信号传导的变化如何通过去除FGF信号的拮抗剂引起的牙齿发育，将导致新见解，这些见解无法通过研究单个FGF配体或其受体的功能丧失突变而获得的新见解。我们的具体目标是：1）研究缺乏SPRY2或SPRY4功能的小鼠，其中牙齿芽在第一个摩尔向前发展成超牙齿。在野生型小鼠中，这些芽会回归以产生无牙的脱水区域。通过分析基因表达，在牙齿器官培养物中进行实验以及分析复杂遗传杂交的后代，我们将确定发芽基因功能的损失如何使疾病牙齿芽持续并发展为牙齿而不是回归。我们的研究将更好地理解蛋白芽在小鼠中形成牙齿以及调节摩尔发育的正常机制。 2）追求我们的观察，即多个发芽等位基因的灭活对门牙的发展具有深远的影响，包括开发重复的切牙。我们建议研究早期切牙的正常形态发生，然后检查该过程如何因发芽基因功能的缺失而受到干扰。 3）确定为什么在Spry2和Null的Spry4杂合子中出现了显着的Tusk样门牙。我们将重点介绍FGF信号在控制胚胎发生过程中控制命运决策以及调节成人祖细胞增殖和分化方面的作用。这些研究的结果将增强我们对控制上皮 - 间质相互作用在器官发生过程中的信号传导途径的理解，并将有助于了解成年小鼠门牙中的干细胞壁nike的知识。 公共卫生的影响：通过我们的研究，我们将进一步了解牙齿正常发展的方式以及这种发育如何在牙科异常患者中出现问题。我们还将研究控制成年牙齿干细胞的机制，这可能有助于为建造新牙齿的努力奠定基础。