Molecular Patterning of Mammalian Dentition

描述（由申请人提供）：发育中的小鼠牙齿长期以来一直被用作研究调节器官发育的分子机制和人类牙齿发育异常的致病机制的强大模型系统。组织重组研究和广泛的突变小鼠模型的遗传分析揭示了一系列的顺序和互惠上皮间质相互作用，涉及多个信号通路和转录因子的规格，启动和形态发生的牙齿器官。尽管许多基因的突变会在不同阶段破坏牙齿发育，但之前报道的小鼠突变中没有一个会导致正常牙列之外的异位牙齿形成。我们发现Odd-skipped-related-2（Osr 2）基因的破坏导致小鼠磨牙舌侧异位多生牙形成，表明Osr 2基因产物在一种新的分子途径中起作用，以形成哺乳动物的牙列。Osr 2-/-突变小鼠也表现出完全的腭裂，另一种常见的人类出生缺陷。Osr 2基因编码进化上保守的锌指转录因子。基因表达分析表明，Osr 2基因在牙齿发育过程中的神经嵴衍生的颅面间充质中表现出动态表达模式。进一步的遗传学研究表明，Osr 2与Bmp 4-Msx 1分子通路相互作用，形成牙齿形态发生场。为了了解Osr 2在哺乳动物牙齿发育和模式控制中的作用及其分子网络，本研究项目将通过表征野生型和Osr 2-/-突变小鼠牙齿发育过程中的表达模式，通过研究异位牙齿起始与正常牙齿发育之间的关系，并通过研究Osr 2与调节牙齿发育的特定分子途径的相互作用。这些研究将大大增加我们对正常牙齿发育和图案遗传控制的分子机制的理解，并将为器官发生的分子机制提供见解，特别是牙齿再生的策略。公共卫生相关性：器官必须在正确的位置以正确的模式发育，以使人体发挥功能。发育中的牙齿已被广泛用作研究器官在何处以及如何发育的模型系统。通过研究几种新的牙齿缺失或多生牙齿的突变小鼠品系，我们发现了一种以前不受重视的控制牙齿发育和模式的机制。从我们的研究中获得的信息将导致对器官发育领域如何控制的理解的重大新进展，以及可以开发哪些新策略来原位再生失去的器官，如牙齿。

DESCRIPTION (provided by applicant): The developing mouse tooth has long been used as a powerful model system for studying the molecular mechanisms regulating organ development and the pathogenic mechanisms of tooth developmental anomalies in humans. Tissue recombination studies and extensive genetic analyses of mutant mouse models have revealed a series of sequential and reciprocal epithelial-mesenchymal interactions involving multiple signaling pathways and transcription factors in the specification, initiation and morphogenesis of the tooth organ. Whereas mutations in many genes disrupt tooth development at various stages, none of the previously reported mutations in mice has caused ectopic tooth formation outside of the normal tooth row. We found that disruption of the Odd-skipped-related-2 (Osr2) gene caused ectopic supernumerary tooth formation lingual to the molars in mice, indicating that the Osr2 gene product functions in a novel molecular pathway to pattern the mammalian dentition. Osr2-/- mutant mice also exhibit complete penetrance of cleft palate, another common birth defect in humans. The Osr2 gene encodes an evolutionarily conserved zinc-finger transcription factor. Gene expression analyses have shown that the Osr2 gene exhibits a dynamic expression pattern in the neural crest-derived craniofacial mesenchyme during tooth development. Further genetic studies showed that Osr2 interacts with the Bmp4-Msx1 molecular pathway to pattern the tooth morphogenetic field. To understand the roles of and the molecular network involving Osr2 in the control of mammalian tooth development and patterning, this research project will clearly define the relationship between Osr2 and the normal tooth developmental molecular program by characterizing the expression patterns during tooth development in wildtype and Osr2-/- mutant mice, by investigating the relationship between ectopic tooth initiation and normal tooth development, and by investigating the interactions of Osr2 with specific molecular pathways regulating tooth development. These studies will greatly increase our understanding of the molecular mechanisms underlying genetic control of normal tooth development and patterning as well as will provide insights to the molecular mechanisms of organogenesis in general and strategies for tooth regeneration in particular. PUBLIC HEALTH RELEVANCE: Organs have to develop in the right place at the right pattern for the human body to function. The developing tooth has been widely used as a model system to study where and how organs develop. By studying several new mutant mouse strains with tooth loss or supernumerary teeth, we have discovered a previously unappreciated mechanism controlling tooth development and patterning. Information gained from our studies will lead to significant new advances in the understanding of how organ developmental fields are controlled and what new strategies can be developed to regenerate lost organs, such as teeth, in situ.