Year: 2014
Type: dissertation
Abstract: Teeth are ectodermal organs, which form from the embryonic epithelium and mesenchyme. Reciprocal interactions between these two tissues, regulated by the conserved signaling pathways, guide tooth morphogenesis. Activity of each signaling pathway is mediated by transcription factors, which activate or repress target genes of the pathway. During morphogenesis, the shape of the dental epithelium undergoes dramatic changes as it proceeds though placode, bud, and cap stages, finally forming the shape of the mature tooth crown. These events are regulated by signaling centers, which are groups of signaling molecule-secreting cells that appear in sequence during tooth development. These include the placode and bud signaling centers, as well as the primary enamel knot and the secondary enamel knots. The location of the enamel knots determines the future tips of the cusps of the tooth crown. In mammals, teeth are replaced only once, whereas most reptiles and fish replace their teeth throughout the life of the animal. Regardless of number of tooth replacements, in all animals, replacement tooth development already begins during morphogenesis of the previous tooth generation. Replacement teeth are initiated from an extension of the epithelium called the successional dental lamina. It forms from a dental lamina that is embedded on the tongue-side epithelium of the primary tooth. Wnt signaling is one of the pathways linked to regulation of tooth replacement both in mammals and in reptiles. In reptiles, tooth replacement has been shown to involve stem cells. However, no markers for these cells have been identified. The aims of this thesis are to study the roles of transcription factors Foxi3 and Sox2 in tooth morphogenesis and replacement, as well as to investigate the molecular regulation of mammalian tooth replacement. A mutation in the gene coding for the transcription factor Foxi3 was identified in hairless dogs, but its function and regulation in ectodermal organ development has not been studied. Here, I showed that Foxi3 is expressed in the dental epithelium. It lies downstream of several signaling pathways including Ectodysplasin, which regulates development of all ectodermal organs. I studied molar development of conditional epithelial Foxi3 knock-out (Foxi3 cKO) mice, and showed that Foxi3 regulates the morphological changes that the dental epithelium undergoes during morphogenesis from bud formation to crown shape patterning by intervening in the activity of several signaling pathways in the signaling centers. The transcription factor Sox2 has been shown to mark the epithelial stem cells of the continuously growing mouse incisor. By combining modern mouse genetics tools with histological and molecular analysis in the ferret and in several reptilian species, I studied how Sox2 is related to the formation of new teeth from the existing dental epithelium. I showed that Sox2 is currently the only gene linked specifically to tooth replacement in mammals and reptiles. Using the mouse molar as a model of successional tooth formation, I showed that Sox2-expressing cells give rise to the epithelium of newly forming teeth, and that Sox2 regulates epithelial proliferation. Sox2 expression during tooth replacement was complementary to Wnt pathway activity, which links stem cell maintenance and initiation of tooth formation. Finally, using the ferret as a model, I characterized the morphology and some aspects of molecular regulation of the mammalian interdental lamina, and show that this non-tooth forming epithelium has characteristics of tooth-forming potential such as Foxi3 and Sox2 expression and Wnt pathway activity. This thesis links two epithelial transcription factors, Foxi3 and Sox2, to the regulation of tooth morphogenesis and formation of new teeth. Knowledge on the function of transcription factors that act downstream of signaling pathways in tooth development and replacement is essential for the understanding of the complex regulation of organ morphogenesis, and can ultimately be applied to the treatment of human syndromes and to the field of tissue regeneration.
Source: Työväentutkimus Vuosikirja
Author: Maria Jussila
Language: English
Subfield: General Dentistry
Field: Dentistry
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2163358153