Wnt signaling in the induction of new tooth formation

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Despite advances in knowledge about tooth morphogenesis and differentiation, relatively little is known about the molecular basis of the induction of tooth formation. My recent studies show that upon epithelial deletion of Ape or activation of Wnt/p-catenin signaling, adult oral tissues, especially young adult tissues, retain odontogenic potential and can still form new teeth, indicating that Ape and Wnt/(3-catenin are key regulatory genes in tooth induction. Moreover, I have found that the induction of supernumerary teeth by Ape deficiency occurs through activation of Wnt/(3-catenin signaling. Once initiated, the development of these new teeth proceeds autonomously to stages of cell differentiation and root formation. My long-term goal is to elucidate the molecular mechanisms that regulate the initiation of tooth formation, thus paving the way for in vitro tooth engineering. The objective of this proposal is to use mRNA and miRNA microarrays to identify the downstream target genes of Wnt/p-catenin signaling, and further analyze their roles and utilize them to induce teeth in vitro. During the K99 mentored phase, I have successfully collected El4.5 tooth germs from >Apc loss of function (LOP) and P-catenin gain of function (GOF) mice, and compared their gene expression profiles using illumina microarray. Consistent with my hypothesis, most genes show concurrent changes in these two mutant mice, and all the genes tested in my previous studies exhibit significant changes in the mutant tooth germs compared to their control littermates. During the ROO independent phase. Aim 1, I will continue working with Biostatisticians to further filter and analyze the microarray data in order to identify the downstream target genes of Wnt/ (3-catenin signaling during tooth initiation. In Aim 2, I will focus on analyzing the role of candidate regulatory genes in tooth initiation using in vitro and in vivo approaches. In Aim 3, I will establish an in vitro culture system to recapitulate the non-cell autonomous effect of Wnt signaling, and will ifurther manipulate the key regulatory genes to induce teeth in vitro. These studies, if successful, will provide fundamental insights into the development of teeth and other organs, and may also assist in tooth engineering in the clinic.