The role of Wnt1 in posteruptive tooth development

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Genetically modified mouse models serve as important tools for analyzing gene functions in vivo and provided the basis for the current molecular understanding of tooth development. Not only does this knowledge help with the diagnosis of dental abnormalities in patients, but it also offers new therapeutic strategies for regenerative dentistry. Of particular interest are the signaling pathways that control the differentiation of stem cells to bone- and tooth-forming cells. Our Institute is specialized on histological and molecular analysis of bone and teeth from mouse models of human genetic bone diseases. It has been recently discovered that forms of osteogenesis imperfecta are caused by mutations in the WNT1 gene. Due to the fact that WNT1 has a central role in the development of tooth-forming neural crest cells, we analyzed the dental phenotype of a mouse model with inducible Wnt1-overexpression.The analysis of 12 week old mice using micro-computed tomography scanning demonstrated a profound osteoanabolic effect of Wnt1 on the jaw. Moreover, histological examinations of 6 week old mice revealed that Wnt1 inhibits dentin formation and promotes cementum formation. Therefore, our hypothesis is that Wnt1 controls differentiation of mesenchymal stem cells to osteoblasts, odontoblasts and cementoblasts. The aim of this grant of the DFG Nachwuchsakademie Zahnmedizin initiative is to characterize the post-natal tooth development in Wnt1-overexpressing mice and to gain first insights into the molecular effects of Wnt1 on differentiation of cementoblasts in vitro.The following questions will be addressed:1) How does Wnt1 regulate root development and tooth eruption? In order to determine the effect of Wnt1 on pre-eruptive tooth development, transgenic mice with immediate post-natal overexpression of Wnt1 will be analyzed by micro-computed tomography, histology and immunohistochemistry.2) How does Wnt1 regulate the quality of bone and tooth tissues and what is the effect of long-term Wnt1 overexpression? The quality and function of bone and tooth tissues in Wnt1-overexpressing mice will be studied using immunohistochemistry and micro-analytical methods. In addition, we will analyze mice with long-term overexpression of Wnt1 (9 weeks).3) How does Wnt1 regulate the differentiation of cementoblasts in vitro? We will treat a cementoblastic cell line (OCCM-30) with a recombinant Wnt1 and analyze these cells using mineralization assays and QPCR analysis of cementoblast differentiation markers.These analyses should provide the basis for a following DFG grant, in which we would like to evaluate the effect of inhibiting Wnt1 and its putative receptors on tooth development in genetically modified mice. Thereby, we could expand the molecular understanding of tooth development and establish the molecular basis for the development of Wnt1-specific drugs in dentistry.