The development of dentition involves a complex series of epithelial-mesenchymal signaling interactions. It is not surprising that such a process is prone to disturbances which then manifest as congenital tooth agenesis in up to 10% of the population and impose significant functional, emotional and financial burdens on patients. Mutations in the paired domain transcription factor, PAX9, contribute to human tooth agenesis. Genetic and molecular studies in mice also indicate a key role for Pax9 in tooth development. Similar to other Pax family members that act in a highly tissue-specific manner, Pax9 is likely to mediate its tooth-specific functions through its interactions with other proteins. Multiple studies point to an important partnership between Pax9 and the Msx1 homeprotein in regulating gene expression in dental mesenchyme. Our long-term goal is to understand how transcription factors like Pax9 mediate key signaling actions in tooth development and how aberrations in Pax9 functions lead to tooth agenesis. The objective of this proposal, which is the next step to accomplish this goal, is to study how Pax9 achieves its selective functions in dental mesenchyme. Based on our preliminary data, we hypothesize that Pax9 maintains the inductive potential of dental mesenchyme through its transactivation functions and protein interactions within a positive feedback loop involving Msx1, Bmp4, and other partner genes. We will achieve our goals by testing the central hypothesis in three specific aims.
Aim 1 will define the molecular basis for the relationship between Pax9, Msx1 and Bmp4. Studies in Aim2 will assess if other candidate genes that are coordinately expressed with Pax9 are involved in the Pax9- Msx1 signaling pathway with Bmp4.
Aim3 will use a human genetics approach to identify additional genes that are responsible for human tooth agenesis and may partner with Pax9 during tooth development. The proposed work is innovative as it capitalizes on a new means to uncover the molecular functions of Pax9 by use of biochemical and human genetics approaches uniquely available in our laboratory. The work will positively impact the field of tooth development by deepening our understanding of the network of interactions that coordinate signaling. Such knowledge may lead to innovative treatments for patients with tooth agenesis including the possibility of bioengineering new teeth.

Public Health Relevance

Congenitally missing teeth are a consequence of gene mutations which interrupt the process of normal toothdevelopment. Only a few of these genes have been identified. We propose to discover additional genes andshow how several of these genes interact in normal tooth development and what disturbs their interaction inpatients with missing teeth.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
7R01DE019471-05
Application #
8770234
Study Section
Special Emphasis Panel (ZRG1-MOSS-K (09))
Program Officer
Scholnick, Steven
Project Start
2008-12-01
Project End
2014-10-31
Budget Start
2013-11-01
Budget End
2014-10-31
Support Year
5
Fiscal Year
2012
Total Cost
$328,579
Indirect Cost
$108,056
Name
University of Utah
Department
Type
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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