GENETIC ANALYSIS OF THE MECHANISMS THAT REGULATE TOOTH MORPHOGENESIS

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DESCRIPTION (provided by applicant): These studies are aimed at understanding the mechanisms that regulate tooth number and morphogenesis. We will take a genetic approach, using mice carrying mutations in Sprouty (Spry) genes, which encode proteins that antagonize signaling via Fibroblast Growth Factors (FGFs). The FGF signaling pathway plays a key role in orchestrating morphogenesis of the tooth as well as many other organs. Analyzing how alterations in FGF signaling perturb tooth development, when these alterations are caused by removing an antagonist of FGF signaling, will lead to new insights that could not be obtained by studying loss-of-function mutations in either individual FGF ligands or their receptors. Our specific goals are: 1) study mice lacking either Spry2 or Spry4 function, in which tooth buds anterior to the first molar develop into supernumerary teeth. In wild-type mice, these buds regress to yield a toothless diastema region. By analyzing gene expression, performing experiments in tooth organ cultures, and by analyzing the progeny of complex genetic crosses, we will determine how loss of Sprouty gene function enables diastema tooth buds to persist and develop into a tooth rather than regress. Our studies will lead to a better understanding of the normal mechanisms by which diastema buds are prevented from forming teeth in the mouse and by which molar development is regulated. 2) pursue our observation that inactivation of multiple Sprouty alleles has profound effects on incisor development, including development of duplicate incisors. We propose to study the normal morphogenesis of early incisors, and then examine how this process is disturbed by deletion of Sprouty gene function. 3) determine why remarkable tusk-like incisors develop in mice that are heterozygous for Spry2 and null for Spry4. We will focus on the role of FGF signaling in controlling fate decisions during embryogenesis and in regulating progenitor cell proliferation and differentiation in the adult. Results from these studies will enhance our understanding of the signaling pathways that control epithelial-mesenchymal interactions during organogenesis and will contribute to knowledge about the stem-cell niche in the adult mouse incisor. Public health implications: Through our studies we will learn more about how teeth normally develop and how this development goes awry in patients with dental abnormalities. We will also study the mechanisms that control stem cells in adult teeth, which may help to lay the groundwork for efforts to build new teeth.