Mechanisms of PITX2 Regulated Tooth Development

描述：我们正致力于建立PITX2在牙齿形态发生过程中的表达、转录活性和蛋白质相互作用的调控机制。PITX2在牙齿发育的最早阶段选择性表达，为研究牙齿形成的分子调控提供了独特的工具。我们对与阿森菲尔德-里格综合征(ARS)相关的PITX2突变的研究为这些患者的牙齿异常提供了分子基础。然而，我们才刚刚开始了解PITX2的分子机制及其在牙齿发育中的作用。我们的总体目标是了解转录因子的级联反应对牙齿发育的协调控制，从PITX2开始。因此，这一提议的重点是了解PITX2激活的靶基因，并确定在时间和空间上调节其转录活性的PITX2相互作用因子。根据我们持续的研究和以前的结果，我们知道PITX2在牙齿发育过程中特异性地调节几个基因的表达，PITX2亚型差异地调节基因的表达。我们已经确定了与PITX2协同作用的因子，以微调这些基因的表达。我们建议验证我们的假设，即PITX2亚型通过特定的3rotein-蛋白质相互作用来差异调节基因的表达。新发现的与ARS患者相关的PITX2 C末端突变将为这些患者的牙齿异常提供新的机制。我们将比较这些F_ITX2突变体和野生型的活性，以确定正常基因表达所需的因子和PITX2转录活性。我们将检验我们的假设，即磷酸化调节蛋白质与PITX2的N末端或C末端区域的相互作用。我们最近发现了一个直接结合PITX2 C末端尾巴的染色质重塑因子，这将是我们研究的重点。我们将检验我们的假设，即PITX2的转录活性在发育过程中通过与该因子的相互作用受到严格调控。这项研究将为发育调节转录因子在胚胎发育高度调控的牙齿发育阶段如何在大量染色质和其他因素中准确激活其目标基因提供一个机制。这些研究将为更好地理解早期牙齿发育的分子控制提供基础。

DESCRIPTION: We are working to establish the regulation of PITX2 expression, transcriptional activities and protein interactions that modulate PITX2 function during tooth morphogenesis. PITX2 provides a unique tool for studying the molecular control of tooth formation since it is selectively expressed at the earliest stage of tooth development. Our work on PITX2 mutations associated with Axenfeld-Rieger syndrome (ARS) has provided a molecular basis for tooth anomalies in these patients. However, we have only begun to understand the molecular mechanisms of PITX2 and its role in tooth development. Our overall goal is to understand the coordinated control of tooth development by the cascade of transcription factors, which starts with PITX2. Therefore, the focus of this proposal is to understand the target genes that are activated by PITX2 and identify PITX2 interacting factors that temporally and spatially modulate its transcriptional activity. Based on our continuing research and previous results we know that PITX2 specifically regulates the expression of several genes during tooth development and PITX2 isoforms differentially modulate gene expression. We have identified factors that act in concert with PITX2 to fine tune the expression of these genes. We propose to test our hypothesis that PITX2 isoforms differentially regulate gene expression through specific 3rotein-protein interactions. Newly identified PITX2 C-terminal mutations associated with ARS patients will provide new mechanisms for the dental anomalies in these patients. We will compare the activities of these F_ITX2mutants to wild type in order to identify factors and PITX2 transcriptional activities required for normal gene expression. We will test our hypothesis that phosphorylation regulates proteins interacting with either the PITX2 N-terminal or C-terminal regions. Our recent identification of a chromatin remodeling factor that directly binds the PITX2 C-terminal tail will be a focus of our studies. We will test our hypothesis that the transcriptional activity of PITX2 is tightly regulated during development by its interaction with this factor. This research will provide a mechanism for how a developmental regulated transcription factor accurately activates its target gene in a sea of chromatin and other factors during the highly regulated phase of tooth development during embryogenesis. These studies will provide the foundation for a better understanding of the molecular control of early tooth development.