Molecular Mechanisms of PITX2 During Craniofacial Development

描述（由申请人提供）：近年来，已经鉴定了许多参与牙齿形态发生的新基因。虽然在识别新基因方面取得了很大进展，并且已经记录了调节牙齿发育的形态发生阶段的信号传导机制，但调节成牙本质细胞和成釉细胞增殖和分化的转录机制知之甚少。更好地了解这一过程的机制方面是必要的，不仅要了解正常的牙齿形态发生，而且要再生牙齿，并最终能够开发和提供更好的治疗策略。PITX 2为研究牙齿形成的分子控制提供了独特的工具，因为它在牙齿发育的最早阶段选择性表达。我们刚刚开始了解PITX 2的分子机制，它在牙齿发育中的作用以及参与颅面/牙齿发育的转录因子的下游层次。这项持续拨款申请的重点是了解PITX 2与其他因素相互作用以调节牙齿发育的分子机制。我们以前的研究结果表明，PITX 2与其他因子一起调节基因表达。我们建议测试我们的假设，PITX 2差异调节基因表达，通过特定的蛋白质-蛋白质相互作用与T盒因子Tbx 1和Tbx 18和LIM同源域因子胰岛-1和Lhx 6。HMG-17是一种染色质相关因子，它将PITX 2募集到活性染色质中，并通过Wnt/β-连环蛋白信号转导被激活。我们将测试我们的假设，即PITX 2的转录活性在发展过程中受到严格的调控，其相互作用与HMG-17，β-catenin，乙酰化组蛋白和染色质重塑因子。微小RNA（miR）对于控制基因表达至关重要，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直接控制门齿和臼齿的图案化，指定了正常颅面/牙齿发育的miR表达的组合代码。我们将测试我们的假设，即在牙齿发育过程中表达的特定miR控制特定转录因子的活性和牙齿的形成。了解这些组成部分如何相互作用，以促进正常颅面发育将进一步我们对遗传缺陷的理解。 公共卫生相关性：颅面/牙齿发育中涉及的新基因的鉴定将增加我们对正常胚胎发生所需的基本发育程序的知识。了解这些组成部分如何相互作用，以促进正常颅面发育将进一步我们对遗传缺陷的理解。然后，我们可以促进方法，以抑制严重的颅面异常，一旦分子基础已被分配到一个特定的缺陷或组件。

DESCRIPTION (provided by applicant): 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's 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. PUBLIC HEALTH RELEVANCE: The identification of new genes involved in craniofacial/tooth development will increase our knowledge about the basic development programs required for normal embryogenesis. Understanding how these components interact to promote normal craniofacial development will further our understanding of genetic defects. We can then promote methodologies to inhibit severe craniofacial anomalies once a molecular basis has been assigned to a specific defect or component.