Molecular mechanisms of PITX2 during craniofacial development

近年来，一些新的基因已经被鉴定出来，这些基因与牙齿的生长有关。 形态发生尽管在鉴定新基因和 调节牙齿发育形态发生阶段的信号机制 已经有文献记载，调节增殖和 成牙本质细胞和成釉细胞的分化知之甚少。更好 了解这一过程的机制方面是必要的，不仅 了解正常的牙齿形态发生，也可以再生牙齿，最终 能够开发和提供更好的治疗策略。PITX 2提供了一个独特的 研究牙齿形成的分子控制的工具，因为它是选择性表达的 在牙齿发育的最早阶段。我们才刚刚开始了解 PITX 2的分子机制，其在牙齿发育中的作用及其下游 转录因子参与颅面/牙齿发育的层次结构。重点 这项持续拨款申请的目的是了解分子机制， PITX 2与其他因子相互作用以调节牙齿发育。我们以前的结果 证明PITX 2与其他因子一起调节基因表达。 我们建议验证我们的假设，即PITX 2差异调节基因表达 通过与T-box因子Tbx 1和Tbx 18的特异性蛋白质-蛋白质相互作用， LIM同源结构域因子Islet-1和Lhx 6。染色质相关因子HMG-17 将PITX 2募集到活性染色质并通过Wnt/β-连环蛋白信号传导被激活。我们 将检验我们的假设，即PITX 2的转录活性受到严格调控， 在发育过程中，通过与HMG-17、β-连环蛋白、乙酰化组蛋白和 染色质重塑因子MicroRNA（miR）是控制基因表达的关键 然而，关于它们在颅面/牙齿发育中的作用知之甚少。 初步数据表明，miR直接控制门牙的图案形成， 臼齿，指定正常颅面/牙齿的miR表达的组合代码 发展我们将验证我们的假设，即特定的miR在牙齿发育过程中表达， 发育控制特定转录因子的活动和 牙齿.了解这些成分如何相互作用，以促进正常颅面 发展将进一步加深我们对遗传缺陷的理解。

In recent years a number of new genes have been identified that are involved in tooth morphogenesis. Though much progress has been made in identifying new genes and the signaling mechanisms that regulate morphogenetic stages of tooth development have been documented, the transcriptional mechanisms that regulate proliferation and differentiation of the odontoblasts and ameloblasts are poorly understood. Better understanding of the mechanistic aspect of this process is necessary, not only to understand normal tooth morphogenesis, but also to regenerate teeth, and eventually be able to develop and deliver better therapeutic strategies. 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. We have only begun to understand the molecular mechanisms of PITX2, its role in tooth development and the downstream hierarchy of transcription factors involved in craniofacial/tooth development. The focus of this continuing grant application is to understand the molecular mechanisms by which PITX2 interacts with other factors to regulate tooth development. Our previous results demonstrate that PITX2 acts in concert with other factors to regulate gene expression. We propose to test our hypothesis that PITX2 differentially regulates gene expression through specific protein-protein interactions with T-box factors Tbx1 and Tbx18 and the LIM homeodomain factors Islet-1 and Lhx6. HMG-17, a chromatin associated factor recruits PITX2 to active chromatin and is activated through Wnt/-catenin signaling. We will test our hypothesis that the transcriptional activity of PITX2 is tightly regulated during development by its interaction with HMG-17, -catenin, acetylated histones and chromatin remodeling factors. MicroRNAs (miR's) are critical to controlling gene expression however little is known about their role in craniofacial/tooth development. Preliminary data demonstrates that miR's directly control the patterning of incisors and molars, specifying a combinatorial code of miR expression for normal craniofacial/tooth development. We will test our hypothesis that specific miR's expressed during tooth development control the activities of specific transcription factors and the patterning of teeth. Understanding how these components interact to promote normal craniofacial development will further our understanding of genetic defects.