Effects of insulin like growth factors on late stages of tooth development

The understanding of the early stages of tooth development has greatly advanced in the past ten years. The late stages of tooth development and differentiation; on the other hand, are less well defined and are the subject of current investigations. Growth factors are believed to be important throughout tooth development. The expression of IGF-I and its cell receptor (IGF-IR) coincides with the expression of genes important for the initiation of tooth mineralization and may play a role in the regulation of their expression. The work presented in this dissertation will attempt to unveil the functions IGFs have in the late stages of tooth development and explore possible mechanisms for their actions. The introduction in Chapter 1 will briefly address tooth evolution in vertebrates followed by a detailed description of the different stages of tooth development and morphogenesis. The introduction will conclude with a brief historical background and characterization of the IGFs as well as a description of the importance that these factors have on tooth development.;This dissertation will test the hypothesis that: IGFs regulate events important for the late stages of tooth differentiation and mineralization. Several sets of experiments were designed to test this hypothesis. First, we looked at the effects IGFs have on proliferation and differentiation on tooth organ cultures. Our results show that IGFs increased enamel and dentine deposition without changes in cell proliferation. This increase was accompanied by the induction of enamelin, amelogenin and collagen type-I while DSPP transcripts were decreased by IGFs. These effects were mirrored in odontoblast-like cells independent from the influence of ameloblasts. Odontoblasts were induced to mineralize by IGFs while the expression of DSPP was inhibited. The possible mechanisms for these actions were explored by looking at the changes in the transcription factor/DNA activities. Our results show changes in the DNA affinity of Brn3, CBF, CREB1, NF-I, NF-E1 and Pbx-1, transcription factors previously demonstrated to be involved in various aspects of tooth development. The results presented in this dissertation strongly suggest the importance IGFs have in late stages of tooth development, highlighting possible mechanisms for their actions.