Proper enamel formation requires coordinated secretion of both structural matrix proteins and proteases along with mineralization to form the hardest and most mineralized tissue in the body. Amelogenins constitute 90% of the organic matrix secreted by ameloblasts and are required for enamel mineralization. Mutations in amelogenin cause Amelogenesis Imperfecta (Al), which is a genetic disorder that causes enamel defects. Different regions of the amelogenin protein are responsible for varying aspects of the enamel mineralization process. Amelogenins are processed by proteolytic enzymes also secreted by ameloblasts, such as MMP20, during enamel formation. The C-terminus of amelogenin is thought to be required for proper formation and assembly of nanospheres, spherical protein aggregates that guide mineral crystal growth, and interaction with hydroxyapatite mineral. To examine the role of the C-terminus of amelogenin in enamel structural integrity using transgenic and amelogenin null mice, this proposal will: 1) determine the effect of the lack of the amelogenin C-terminus on enamel microstructure and nanomechanical properties;2) determine the importance of MMP20 processing of amelogenin at the C-terminus on enamel microstructure, nanomechanical properties, and organic matrix removal;and 3) examine rod organization and ameloblast Tomes'process morphology in mice with an amelogenin C-terminal mutation.

Public Health Relevance

This research will contribute to the current knowledge of the role of enamel matrix proteins in enamel development and mineralization. Analysis of transgenic mouse models with mutations in amelogenin and other enamel matrix genes can lead to increased understanding of different Al phenotypes and their corresponding genetic mutations in patients. As a result, clinical treatments and approaches for humans with Al and other enamel disorders can be improved.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDE1-MK (18))
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Frieden, Leslie A
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University of Pennsylvania
Anatomy/Cell Biology
Schools of Dentistry
United States
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Pugach, M K; Suggs, C; Li, Y et al. (2013) M180 amelogenin processed by MMP20 is sufficient for decussating murine enamel. J Dent Res 92:1118-22
Xue, Hui; Li, Yong; Everett, Eric T et al. (2013) Ameloblasts require active RhoA to generate normal dental enamel. Eur J Oral Sci 121:293-302
Li, Yong; Pugach, Megan K; Kuehl, Melissa A et al. (2011) Dental enamel structure is altered by expression of dominant negative RhoA in ameloblasts. Cells Tissues Organs 194:227-31
Pugach, M K; Ozer, F; Li, Y et al. (2011) The use of mouse models to investigate shear bond strength in amelogenesis imperfecta. J Dent Res 90:1352-7
Pugach, M K; Li, Y; Suggs, C et al. (2010) The amelogenin C-terminus is required for enamel development. J Dent Res 89:165-9