Molecular Patterning of Mammalian Dentition

描述(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。组织重组研究和对突变小鼠模型的广泛遗传分析揭示了在牙齿器官的指定、起始和形态发生中涉及多个信号通路和转录因子的一系列顺序和相互作用的上皮-间充质相互作用。虽然许多基因的突变会在不同的阶段扰乱牙齿的发育，但之前在小鼠身上报告的突变都没有导致正常牙排以外的异位牙齿形成。我们发现OSR2(Odd-Skiped-Related-2，OSR2)基因的缺失导致了小鼠磨牙舌侧的异位多生牙形成，表明OSR2基因产物在哺乳动物牙列模式的新的分子途径中发挥作用。OSR2-/-突变小鼠也表现出完全的腭裂外露，这是人类另一种常见的出生缺陷。OSR2基因编码一种进化上保守的锌指转录因子。基因表达分析表明，OSR2基因在牙齿发育过程中神经沟来源的颅面间充质中呈现动态表达模式。进一步的遗传学研究表明，OSR2与Bmp4-Msx1分子通路相互作用，形成牙齿形态发生场。为了了解OSR2在哺乳动物牙齿发育和构型调控中的作用和涉及的分子网络，本研究项目将通过研究野生型和OSR2-/-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和正常牙齿发育的关系，以及通过研究OSR2与调控牙齿发育的特定分子途径的相互作用，明确OSR2与正常牙齿发育分子程序的关系。这些研究将大大增加我们对正常牙齿发育和形态遗传控制的分子机制的理解，并将为器官发生的分子机制，特别是牙齿再生的策略提供深入的见解。与公共健康相关：器官必须在正确的位置、正确的模式下发育，人体才能发挥作用。发育中的牙齿已经被广泛地用作研究器官在哪里以及如何发育的模型系统。通过研究几个新的牙齿缺失或多余牙齿的突变小鼠品系，我们发现了一种以前未被认识到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在理解器官发育领域是如何控制的以及可以开发哪些新的策略来原位再生丢失的器官(如牙齿)方面取得重大的新进展。

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.