Molecular Patterning of Mammalian Dentition

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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.