PROJECT SUMMARY/ABSTRACT Enamel is the outer covering of teeth and is unique in that it is the hardest tissue in our body and one of the few human tissues that cannot regenerate. This inability for human enamel to regenerate is attributed to the loss of ameloblasts or enamel-forming cells and their precursor cells upon eruption of teeth into the oral cavity. Thus, it would be powerful if we could direct adult stem cells that normally do not produce enamel to differentiate into ameloblasts and unravel the molecular mechanisms involved. Two novel genetically modified mouse lines developed in my laboratory allows us to induce inactivation of the Isl1 gene (which leads to ectopic enamel formation in adult mice) or deletion of cells expressing Isl1 (which allows us to remove putative dental epithelial stem cells for functional analysis). By analyzing context dependent roles of Isl1 during mouse incisor renewal, we will advance our molecular and cellular understanding of stem cell specification, ameloblast differentiation, and enamel mineralization - pre-requisite for future innovations and improvements to current diagnostic, preventive, and therapeutic methods in dentistry.