Research Project Background

Tooth shape and crown morphology are essential characteristics of each tooth type and are directly linked to functions such as mastication, speech, and facial esthetics. Over 300 genetic syndromes have dental structural defects as phenotypic traits. In addition there are non-syndromic inherited conditions affecting tooth development, such as dentinogenesis imperfecta, dentin dysplasia, and amelogenesis imperfecta. Treatment of these conditions places a heavy social-economical burden on affected families. Biomedical approaches and cures can only replace dental restorative procedures after the genetics and developmental biology of these conditions are understood. In the case of dental enamel formation, proteomics and genetic analyses of developing teeth have identified the extracellular matrix proteins involved and identified the genes encoding them, but these genes account for only 25% of non-syndromic inherited enamel defects. The rest of the genes are believed to be involved in specialized processes within ameloblasts (the cells responsible for enamel biomineralization) and in the regulation and control of ameloblast differentiation and activities. The regulation and control of enamel formation (amelogenesis) is complex and current approaches have done little to increase our understanding of it. Innovative approaches are necessary for success.

Dental enamel is the hardest tissue in vertebrates and teeth are the most frequently preserved remains after death. Stored within the microscopic structure of teeth is a detailed record of daily growth. The most useful data preserved in teeth are incremental growth lines that mark the enamel and dentin surfaces for each day during development, permitting the developmental and chronological history of a crown to be accurately reconstructed. There are short-period (1 day) and long-period (~1 week) lines in enamel and dentin. Interpretations in dentistry, forensics, archaeology, anthropology, and paleontology are currently based on analyses of incremental lines in teeth. However, the biological links between the enamel incremental growth lines and specific ameloblast gene expression and ameloblast differentiation steps are missing.

Research Hypothesis

This research starts from the perspective that the shape of an enamel crown results from five morphogenetic growth parameters that are under strict biological control during amelogenesis:

1) the appositional growth rate,

2) the duration of appositional growth (at the cusp tip),

3) the extension rate,

4) the duration of ameloblast extension, and

5) the spreading rate of appositional termination.

These growth parameters are not constant, but are regulated by ameloblasts during crown formation. It is possible to measure these growth parameters and determine how they vary during enamel crown formation by analyzing the incremental growth lines “fossilized” within the enamel structure during development. Additionally, there is a direct correlation between the specific gene expression synchronized with the growth and morphogenesis of the enamel layer, the ameloblast differentiation steps, and the five morphogenetic growth parameters.

Specific Aims

Our first aim is to determine how these parameters work together to determine the shape of the enamel crown through mathematical modeling and 2D and 3D simulations. This has never before been attempted, but is the best way to grasp how multiple simultaneously varying growth parameters achieve the crown shapes observed in human teeth. Furthermore, the modeling will provide insight into the nature of the biological mechanisms that control the five morphogenetic growth parameters.

Our second aim is to investigate common regulatory motifs that govern the synchronized expression (transcriptional onset and silencing) of genes representative of specific stages of enamel formation to identify the cellular and differentiation factors that regulate the five morphogenetic growth parameters and determine tooth shape.

Significance and Outcome

This model will show precisely when during crown formation the five growth parameters are regulated. Information gained from the 3D computer simulations and complementary innovative experimental approaches will be used to discover the regulatory pathways and networks that orchestrate the differentiation of ameloblasts and enamel formation. Such knowledge will allow us to better understand developmental processes that control tooth shape in development, evolution, and diseases and ultimately to help people with developmental and genetic anomalies by laying the foundation for innovative dental treatments.

Collaborations

Collaborators at the UM campus include Dr. Daniel Fisher, professor of geological sciences and curator of the Museum of Paleontology and Dr. James Simmer, professor of dentistry in the department of biological and materials sciences. Individuals with background and interest in developmental biology and/or computer modeling that may be interested in participating in any aspect of our projects are welcome to contact us.