Molecular mechanisms of PITX2 during craniofacial development

PITX2在颅面发育过程中的分子机制

• 批准号: 8550273
• 负责人: BRAD A AMENDT
• 金额: $ 37万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8550273
• 关键词: Molecular; mechanisms; PITX2; during; craniofacial

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.

近年来，人们发现了许多与牙齿有关的新基因。 形态发生。尽管在识别新基因和新基因方面取得了很大进展 调控牙齿发育形态发生阶段的信号机制 已经被记录在案，调控增殖和 成牙本质细胞和成釉细胞的分化尚不清楚。更好 了解这一过程的机制方面是必要的，不仅是为了 了解正常的牙齿形态发生，也要再生牙齿，并最终 能够开发和提供更好的治疗策略。PITX2提供了独特的 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 PITX2的分子机制及其在牙齿发育和下游中的作用 参与颅面/牙齿发育的转录因子的层次结构。焦点 这项持续的拨款申请的关键是了解 PITX2与其他因素相互作用，调节牙齿发育。我们之前的结果 证明PITX2与其他因子协同作用调节基因表达。 我们建议检验我们的假设，即PITX2差异调节基因表达 通过与T-box因子TBX1和TBX18的特定蛋白质相互作用 LIM同源结构域因子Islet-1和Lhx6。染色质相关因子HMG-17 招募PITX2为活性染色质，并通过Wnt/-catenin信号被激活。我们 将检验我们的假设，即PITX2的转录活性受到严格调控 在发育过程中，通过与HMG-17，-连环蛋白，乙酰化组蛋白和 染色质重塑因子。MicroRNAs(miR‘s)是控制基因的关键 然而，人们对它们在颅面/牙齿发育中的作用知之甚少。 初步数据显示，miR直接控制门牙的图案和 磨牙，为正常颅面/牙齿指定miR表达的组合代码 发展。我们将检验我们的假设，即特定的miR在牙齿中表达 发育控制特定转录因子的活性和模式的形成 牙。了解这些成分如何相互作用促进正常的颅面 发展将进一步加深我们对基因缺陷的理解。