To the root of the stem cell problem - The evolutionary importance of the epithelial stem cell niche during tooth development

To the root of the stem cell problem - The evolutionary importance of the epithelial stem cell niche during tooth development
September 2004
By Mark Tummers, Developmental Biology Programme Institute of Biotechnology. University of Helsinki and Viikki Graduate School in Biosciences, University of Helsinki - Academic Dissertation
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SUMMARY
A tooth is an ectodermal organ and its development relies on epithelial-mesenchymal interactions that are mediated by conserved signalling pathways common to other developmental processes. During the transition from the bud to the cap stage the cervical loop is formed. This structure will later become the adult epithelial stem cell niche in continuously growing teeth, such as the mouse incisor. Notch signalling is involved in demarcating the boundary between the enamel knot, the signalling center of the tooth, and the remainder of the epithelial compartment. There is a sharp boundary of Lunatic fringe (a Notch receptor modulator) first at the lingual side and later also at the buccal side of the enamel knot. Lunatic fringe may play a role in boundary formation of the enamel knot and Notch signalling in the epithelium is regulated by mesenchymal FGFs and BMPs. The enamel knot subsequently directs the formation of the cervical loop.
The cervical loop has the specific structure of centrally located stellate reticulum surrounded by a basal layer of epithelium. The stellate reticulum is the putative site for the adult stem cells. In continuously growing teeth such as the mouse incisor and the sibling vole molar this structure and the regulatory system of epithelial Notch and mesenchymal FGF signalling is maintained. In non-continuously growing teeth, such as the low-crowned molar of the mouse, the stellate reticulum disappears and FGF and Notch signalling are downregulated. BMP signalling plays an important role in the epithelial-mesenchymal interactions during early tooth development. However, neither BMPs nor any of the MSX transcription factors seem to have an important role in guiding root formation. It is therefore not clear how the growth of the root is directed after losing the stem cell niche.
The regulation of the epithelial stem cell niche seems highly flexible and allows for evolutionary novelty. Different tooth types can be generated by merely extending the maintenance of the stem cell niche: in low-crowned teeth the stem cell niche is maintained shortly resulting in a low crown, in high-crowned teeth the maintenance is extended resulting in a longer growth period of the crown, and in continuously growing teeth the stem cell niche is maintained indefinitely.
There are two major types of continuously growing teeth: continuously growing ÇƒÚcrownsÇƒÙ and ÇƒÚrootsÇƒÙ. The continuously growing root is a rare tooth found in the Edentates, such as the sloth. In the transgenic k14-Eda overexpressing mouse the continuously growing incisor is transformed from the ÇƒÚcrownÇƒÙ type into the ÇƒÚrootÇƒÙ type, and is similar to the sloth in structure and histology. The stem cell niche does not adopt the typical root structure known as HertwigÇƒÙs epithelial root sheath (HERS) as can be seen for instance in mouse molars. Instead it maintains its stellate reticulum and the typical molecular regulatory setup of Notch and FGF signalling that is found in continuously growing crowns. The root fate is therefore not automatically linked to HERS, and a functional stem cell niche is not necessarily associated with crown formation. This regulatory flexibility allows for patterning flexibility of the proximal-distal axis of the tooth. Teeth are flexible in their regulation of crown height, resulting in different ratios of crown and root surface. And teeth can also do a merely partial conversion of the crown in a root surface, creating teeth like the rodent incisor with enamel on the front (crown) and dentin on the back (root) of the tooth. The independence of the regulation of the stem cell niche and of differentiation has allowed for developmental flexibility and evolutionary variation in tooth character.