The zebrafish has been used extensively as a model for the genetics of development and human disease, but has yet to be exploited fully for studies of the dentition. The proposed research seeks to contribute to the establishment of the zebrafish as a model for tooth development. The molecular subjects of the proposed research, ligands and receptors in the Fibroblast growth factor (Fgf) signaling pathway, have been shown to be required for tooth development in the mouse and one pathway component has recently been linked to human tooth agenesis. Fgf ligands and receptors are known to act at multiple stages of tooth development, but it is likely that additional roles remain to be discovered. The proposed research is an attempt to uncover such roles through identification of dentally-expressed Fgf receptors and ligands in the zebrafish, followed by the use of morpholino antisense oligonucleotides (MOs) to block translation or splicing of their transcripts. The expression of all four known zebrafish Fgf receptors and at least ten Fgf ligands will examined by in situ hybridization and MOs will be designed to target those found to be expressed in odontogenic regions. Such design will require obtaining some additional sequence data from public databases or through gene cloning. MO-injected zebrafish will be examined for altered tooth development by both skeletal staining and in situ hybridization approaches. It is anticipated that phenotypic effects of """"""""knocking down"""""""" the expression of some of these Fgf receptors and ligands will range between those already obtained (altered tooth shape and tooth agenesis accompanied by severe disruption of the development of the pharyngeal region). Genes found to be required for tooth development will be the subject of a future proposal submission for more detailed characterization of their roles. It is hoped that by identifying the roles played by the Fgf signaling pathway in zebrafish tooth development, insight will be gained into fundamental mechanisms of mammalian tooth development as well as the causes of human genetic dental abnormalities.
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