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: 7886777
• 负责人: GAIL R. MARTIN
• 金额: $ 35.62万
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7886777
• 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(申请人提供)：这些研究旨在了解调控牙齿数量和形态发生的机制。我们将采取遗传方法，使用携带Sprouty(Spry)基因突变的小鼠，Sprouty基因编码的蛋白质通过成纤维细胞生长因子(FGFs)拮抗信号。成纤维细胞生长因子信号通路在协调牙齿和许多其他器官的形态发生中起着关键作用。当这些变化是由于移除了成纤维细胞生长因子信号的拮抗剂而引起的，分析成纤维细胞生长因子信号的变化是如何扰乱牙齿发育的，将带来新的见解，这是通过研究单个成纤维细胞生长因子配体或其受体的功能丧失突变所无法获得的。我们的具体目标是：1)研究缺乏SPRY2或SPRY4功能的小鼠，在这些小鼠中，第一颗磨牙前面的牙芽发育成多余的牙齿。在野生型小鼠中，这些芽会退化，产生一个没有牙齿的间隔区域。通过分析基因表达，在牙齿器官培养中进行实验，以及通过分析复杂遗传杂交的后代，我们将确定Sprouty基因功能的丧失如何使间隔牙芽持续并发育成牙齿，而不是退化。我们的研究将有助于更好地理解在小鼠体内阻止间隔芽形成牙齿和调节磨牙发育的正常机制。2)继续我们的观察，多个Sprouty等位基因的失活对门牙发育有深远的影响，包括重复门牙的发育。我们建议研究早期门牙的正常形态发生，然后研究Sprouty基因功能缺失是如何干扰这一过程的。3)确定为什么在SPRY2杂合子和SPRY4杂合子的小鼠身上发育出显著的象牙一样的门牙。我们将重点介绍成纤维细胞生长因子信号在胚胎发育过程中控制命运的作用，以及在成体中调控祖细胞增殖和分化的作用。这些研究的结果将加深我们对器官发生过程中控制上皮-间充质相互作用的信号通路的理解，并将有助于了解成年小鼠切牙的干细胞生态位。 对公众健康的影响：通过我们的研究，我们将更多地了解牙齿是如何正常发育的，以及牙齿异常患者的这种发育是如何出错的。我们还将研究成人牙齿中干细胞的控制机制，这可能有助于为建造新牙齿的努力奠定基础。