Signaling Mechanisms in Early Tooth Development

描述（由申请人提供）：牙列发育涉及一系列复杂的上皮-间充质信号相互作用。这并不奇怪，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，并给患者带来重大的功能，情感和经济负担。配对结构域转录因子PAX 9的突变导致人类牙齿发育不全小鼠的遗传和分子研究也表明Pax 9在牙齿发育中起着关键作用。与其他以高度组织特异性方式起作用的Pax家族成员类似，Pax 9可能通过与其他蛋白质的相互作用来介导其牙齿特异性功能。多项研究指出Pax 9和Msx 1 homeprotein在调节牙齿间充质中的基因表达中的重要伙伴关系。我们的长期目标是了解Pax 9等转录因子如何介导牙齿发育中的关键信号传导作用，以及Pax 9功能的异常如何导致牙齿发育不全。该提案的目标是实现这一目标的下一步，即研究Pax 9如何在牙齿间充质中实现其选择性功能。基于我们的初步数据，我们假设Pax 9通过其反式激活功能和蛋白质相互作用在涉及Msx 1，Bmp 4和其他伙伴基因的正反馈回路中保持牙齿间充质的诱导潜力。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将定义Pax 9，Msx 1和Bmp 4之间关系的分子基础。Aim 2的研究将评估与Pax 9协同表达的其他候选基因是否参与了Bmp 4的Pax 9-Msx 1信号通路。Aim 3将使用人类遗传学方法来确定负责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Pax 9合作。拟议的工作是创新的，因为它利用了一种新的手段，通过使用我们实验室独有的生物化学和人类遗传学方法来揭示Pax 9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。 公共卫生相关性：先天性缺牙是基因突变的结果，基因突变中断了正常的牙齿发育过程。这些基因中只有少数被发现。我们建议发现更多的基因，并显示这些基因中的几个如何在正常的牙齿发育中相互作用，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.