Enamel is the first and main line of defense against dental decay, and its proper formation is a prerequisite for strong, healthy teeth. Abnormalities in the molecular and cellular pathways that drive enamel formation (amelogenesis) result in amelogenesis imperfecta, a broad designation for a number of non-syndromic and syndromic enamel defects. A better mechanistic understanding of amelogenesis is important to devise new and improved strategies in the prevention, diagnosis, and treatment of dental caries and inherited disorders such as amelogenesis imperfecta. Because enamel is unique amongst mineralized tissues in its epithelial origin, genes involved in epithelial development and integrity such as Perp are excellent candidate regulators of amelogenesis. PERP (P53-effector related to PMP-22) is a membrane protein that plays an essential role in the stable assembly of desmosomes, which are cell-cell adhesion macromolecules central to epithelial integrity and homeostasis. I have recently found that inactivation of Perp leads to enamel defects, in part, due to the detachment of ameloblasts from the underlying stratum intermedium (SI) layer. The ameloblast-SI interface is an area of co-localization between PERP and desmosomes, and high magnification images revealed desmosomal defects. In addition, a large number of differentially regulated genes in the teeth of Perp-null mice was identified. Several of these genes are previously characterized regulators of amelogenesis but the majority has never been shown to play a role in this process. Beyond my initial studies, little is known about the function and regulation of Perp in amelogenesis. In this application, I propose to test the hypothesis that the function and regulation of Perp play a central role in amelogenesis. This will be done by the analyses of antibody-treated mice and various mouse genetic models, as well as experiments using cell culture. Successful completion of these studies is important for issues of human oral health related to proper tooth development.

Public Health Relevance

Enamel is the outer layer of teeth that is the main line of defense against dental decay, and its proper formation is a prerequisite for strong, healthy teeth. In light of the fact that enamel is one of the few tissues in our bodies that is not capable of regeneration, a better mechanistic understanding of enamel formation is important to potentially devise new and improved strategies in the prevention, diagnosis, and treatment of dental caries and other tooth-related disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Transition Award (R00)
Project #
5R00DE022059-04
Application #
8723644
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Lumelsky, Nadya L
Project Start
2013-08-20
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Zhang, Bin; Meng, Bo; Viloria, Edward et al. (2018) The Role of Epithelial Stat3 in Amelogenesis during Mouse Incisor Renewal. Cells Tissues Organs 205:63-71
Prochazkova, Michaela; Häkkinen, Teemu J; Prochazka, Jan et al. (2017) FGF signaling refines Wnt gradients to regulate the patterning of taste papillae. Development 144:2212-2221
Zheng, X; Goodwin, A F; Tian, H et al. (2017) Ras Signaling Regulates Stem Cells and Amelogenesis in the Mouse Incisor. J Dent Res 96:1438-1444
Naveau, Adrien; Zhang, Bin; Meng, Bo et al. (2017) Isl1 Controls Patterning and Mineralization of Enamel in the Continuously Renewing Mouse Incisor. J Bone Miner Res 32:2219-2231
Jheon, Andrew H; Prochazkova, Michaela; Meng, Bo et al. (2016) Inhibition of Notch Signaling During Mouse Incisor Renewal Leads to Enamel Defects. J Bone Miner Res 31:152-62
Jheon, Andrew H; Prochazkova, Michaela; Sherman, Michael et al. (2015) Spontaneous emergence of overgrown molar teeth in a colony of Prairie voles (Microtus ochrogaster). Int J Oral Sci 7:23-6
Goodwin, Alice F; Larson, Jacinda R; Jones, Kyle B et al. (2014) Craniofacial morphometric analysis of individuals with X-linked hypohidrotic ectodermal dysplasia. Mol Genet Genomic Med 2:422-9
Chavez, Miquella G; Hu, Jimmy; Seidel, Kerstin et al. (2014) Isolation and culture of dental epithelial stem cells from the adult mouse incisor. J Vis Exp :
Goodwin, Alice F; Tidyman, William E; Jheon, Andrew H et al. (2014) Abnormal Ras signaling in Costello syndrome (CS) negatively regulates enamel formation. Hum Mol Genet 23:682-92
Hall, Jane; Jheon, Andrew H; Ealba, Erin L et al. (2014) Evolution of a developmental mechanism: Species-specific regulation of the cell cycle and the timing of events during craniofacial osteogenesis. Dev Biol 385:380-95

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