Signaling Mechanisms in Early Tooth Development

描述(由申请人提供)：牙列的发育涉及一系列复杂的上皮-间充质信号相互作用。毫不奇怪，这样的过程容易出现障碍，然后在高达10%的人口中表现为先天性牙齿发育不全，并给患者带来巨大的功能、情感和经济负担。成对结构域转录因子PAX9的突变与人类牙齿发育不全有关。对小鼠的遗传学和分子研究也表明，Pax9在牙齿发育中起着关键作用。与其他高度组织特异性的Pax家族成员类似，Pax9可能通过与其他蛋白质的相互作用来调节其牙齿特异性功能。多项研究表明，Pax9和Msx1同源蛋白在调节牙齿间充质中的基因表达方面存在重要的合作关系。我们的长期目标是了解像Pax9这样的转录因子是如何在牙齿发育中介导关键信号活动的，以及Pax9功能异常是如何导致牙齿发育不全的。这项建议的目的是研究Pax9如何在牙间充质中实现其选择性功能，这是实现这一目标的下一步。根据我们的初步数据，我们假设Pax9通过其反式激活功能和涉及Msx1、Bmp4和其他伙伴基因的正反馈环中的蛋白质相互作用来维持牙齿间充质的诱导潜能。我们将通过在三个具体目标中检验中心假设来实现我们的目标。目的1将确定Pax9、Msx1和Bmp4之间关系的分子基础。对AIM2的研究将评估与Pax9协调表达的其他候选基因是否参与了与Bmp4的Pax9-Msx1信号通路。Aim3将使用人类遗传学方法来识别导致人类牙齿发育不全的其他基因，并可能在牙齿发育过程中与Pax9合作。这项拟议的工作具有创新性，因为它利用了一种新的方法，通过使用我们实验室独特的生化和人类遗传学方法来揭示Pax9的分子功能。这项工作将通过加深我们对协调信号的相互作用网络的理解，对牙齿发育领域产生积极的影响。这些知识可能会导致牙齿发育不全患者的创新治疗，包括生物工程新牙齿的可能性。 与公共卫生相关：先天缺失的牙齿是基因突变的结果，基因突变会中断正常的牙齿发育过程。这些基因中只有几个已经被识别出来。我们建议发现更多的基因，并展示这些基因中的几个在正常牙齿发育中是如何相互作用的，以及是什么干扰了缺牙患者的相互作用。

DESCRIPTION (provided by applicant): The development of dentition involves a complex series of epithelial-mesenchymal signaling interactions. It is not surprising that such a process is prone to disturbances which then manifest as congenital tooth agenesis in up to 10% of the population and impose significant functional, emotional and financial burdens on patients. Mutations in the paired domain transcription factor, PAX9, contribute to human tooth agenesis. Genetic and molecular studies in mice also indicate a key role for Pax9 in tooth development. Similar to other Pax family members that act in a highly tissue-specific manner, Pax9 is likely to mediate its tooth-specific functions through its interactions with other proteins. Multiple studies point to an important partnership between Pax9 and the Msx1 homeprotein in regulating gene expression in dental mesenchyme. Our long-term goal is to understand how transcription factors like Pax9 mediate key signaling actions in tooth development and how aberrations in Pax9 functions lead to tooth agenesis. The objective of this proposal, which is the next step to accomplish this goal, is to study how Pax9 achieves its selective functions in dental mesenchyme. Based on our preliminary data, we hypothesize that Pax9 maintains the inductive potential of dental mesenchyme through its transactivation functions and protein interactions within a positive feedback loop involving Msx1, Bmp4, and other partner genes. We will achieve our goals by testing the central hypothesis in three specific aims. Aim 1 will define the molecular basis for the relationship between Pax9, Msx1 and Bmp4. Studies in Aim2 will assess if other candidate genes that are coordinately expressed with Pax9 are involved in the Pax9- Msx1 signaling pathway with Bmp4. Aim3 will use a human genetics approach to identify additional genes that are responsible for human tooth agenesis and may partner with Pax9 during tooth development. The proposed work is innovative as it capitalizes on a new means to uncover the molecular functions of Pax9 by use of biochemical and human genetics approaches uniquely available in our laboratory. The work will positively impact the field of tooth development by deepening our understanding of the network of interactions that coordinate signaling. Such knowledge may lead to innovative treatments for patients with tooth agenesis including the possibility of bioengineering new teeth. PUBLIC HEALTH RELEVANCE: Congenitally missing teeth are a consequence of gene mutations which interrupt the process of normal tooth development. Only a few of these genes have been identified. We propose to discover additional genes and show how several of these genes interact in normal tooth development and what disturbs their interaction in patients with missing teeth.