The function of Hedgehog signaling in maintaining the dental mesenchymal stem cells

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Abstract Dental mesenchymal stem cells are an important group of cells, which are critical for tooth development, homeostasis and response to injury repairs. Recent studies have demonstrated that in the mouse incisor, Gli1- LacZ positive cells contribute to continuously supplying odontoblasts for dentin formation. However, the exact function of Hedgehog signaling in regulating the dental mesenchymal stem cells remained to be elusive. EvC syndrome is an autosomal recessive chondrodysplasia. Studies form our group and others have demonstrated that the causative genes for EvC syndrome, Evc and Evc2, are positive regulators of Hedgehog signaling. Our recent work also demonstrates that Evc2 loss of function in the dental mesenchyme leads to delayed odontoblast differentiation. In the proposed works here, we will use Evc2 mutant mice as models to characterize the function of Hedgehog signaling in regulating the dental mesenchymal stem cells. Given the preliminary data and the recent studies, we hypothesize that Hedgehog signaling promote differentiation of glial progenitor cells to odontoblast progenitor cells and that incompetent odontoblast progenitor cells due to Evc2 loss of function leads to delayed odontoblast differentiation. Our hypothesis will be examined by the following two aims: 1) Demonstrate that Hedgehog signaling in the dental mesenchyme is important for odontoblast progenitor cell number and competence during development; 2) Demonstrate Hedgehog signaling in the glial progenitor cells is critical for subsequent differentiation to odontoblast progenitor cells. The outcome of the proposed work will uncover the patho-physiological mechanism leading to tooth abnormalities in Ellis- van Creveld (EvC) syndrome and provide knowledge for supporting future tooth regeneration studies.