New Molecules and Cures for Tooth Agenesis

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PROJECT SUMMARY The development of dentition is a highly complex process that involves a series of reciprocal epithelial- mesenchyme interactions that are regulated by five conserved signaling pathways, namely Bmp, Fgf, Wnt, Eda and Shh. That such a precise process is often perturbed is not surprising. Indeed, tooth agenesis is one of the most commonly inherited human disorders that affects up to 10% of the population and imposes significant burdens on patients and their families. Mutations in PAX9, a paired-domain transcription factor that is specifically expressed in dental mesenchyme, cause human tooth agenesis. The deletion of Pax9 in mice leads to tooth arrest at the bud stage, thus underscoring its key inductive role within dental mesenchyme. Better understanding the molecular actions of Pax9 in dental mesenchyme during the induction phase of tooth morphogenesis offers hope for the development of tangible therapies that can benefit patients with tooth agenesis. Our microarray analyses of Pax9-/- tooth organs show that Wnt signaling genes are most markedly altered along with the Bmps, Fgfs, Shh and Eda-related genes. The results of our human genetic analyses and data from other groups confirm that mutations in WNT10A are responsible for the majority of cases of human tooth agenesis. Significantly, our preliminary experiments suggest that Wnt agonists, when administered to pregnant Pax9+/- mothers, are able to rescue the mutant phenotype of cleft palate and tooth arrest. Despite these advances there is little understood about the precise molecular relationship of Pax9 with the Wnt signaling pathway in dental mesenchyme and how such basic science knowledge can be translated into new advances for the treatment of human tooth agenesis. Taken together, our data provide the framework for studies that will systematically test the hypothesis that Pax9 is a key modulator of signaling events in dental mesenchyme during early tooth morphogenesis through its regulation of genes in the Wnt pathway. The restoration of Wnt signaling in Pax9 and Wnt10a mutant dental mesenchyme is hence likely to normalize tooth morphogenesis. Aim 1 studies will use multipronged approaches to provide new data on the molecular relationship of Pax9 with genes that regulate Wnt signaling activities in dental mesenchyme during early morphogenesis since this relationship is not as well studied as that with the Bmp and Fgf pathways. Aim 2 will test how human tooth agenesis-causing mutations in Pax9 and Wnt10A affect the functional relationship of these genes to result in an arrest in tooth development. Aim 3 will confirm the upstream relationship of Pax9 by assessing whether novel Wnt-based therapeutics when administered in-vivo, can correct the Pax9-/- tooth agenesis phenotype through a restoration of Wnt function. Data from these basic science and translational studies will advance our understanding about the signaling molecules in dental mesenchyme and will provide the framework for developing and testing non-invasive therapies to restore tooth development in humans affected by non-syndromic tooth agenesis, an important problem of high clinical relevance and for which there are no cures.