GENETIC ANALYSIS OF THE MECHANISMS THAT REGULATE TOOTH MORPHOGENESIS

描述（由申请人提供）：这些研究旨在了解调节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，该基因编码通过成纤维细胞生长因子（FGF）拮抗信号传导的蛋白质。FGF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。分析FGF信号传导的改变如何干扰牙齿发育，当这些改变是由去除FGF信号传导的拮抗剂引起时，将导致新的见解，这是通过研究单个FGF配体或其受体的功能丧失突变无法获得的。我们的具体目标是：1）研究缺乏Spry 2或Spry 4功能的小鼠，其中第一磨牙前的牙芽发育成多生牙。在野生型小鼠中，这些芽退化产生无齿的间隙区域。通过分析基因表达，在牙齿器官培养中进行实验，并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牙间隙牙芽持续并发育成牙齿而不是退化。我们的研究将导致更好地理解的正常机制，其中牙间隙芽是防止形成牙齿的小鼠和磨牙发育的调节。2)继续我们的观察，即多个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，然后研究这个过程是如何被Sprouty基因功能缺失所干扰的。3)确定为什么显着的象牙状门牙发展的小鼠是杂合子的Spry 2和无效的Spry 4。我们将重点关注FGF信号在胚胎发生过程中控制命运决定和在成人中调节祖细胞增殖和分化的作用。这些研究的结果将提高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中的干细胞生态位。 对公共卫生的影响：通过我们的研究，我们将更多地了解牙齿如何正常发育，以及牙齿异常患者的牙齿发育如何出错。我们还将研究控制成年牙齿中干细胞的机制，这可能有助于为构建新牙齿奠定基础。

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.