February 2002

NIDCR Scientists Create Mouse Model for Dental Defect
First "Knockout" Animal Model for Tooth-Specific Gene

Scientists at the National Institute of Dental and Craniofacial Research (NIDCR) have created an animal model for amelogenesis imperfecta, a dental defect which results in abnormally formed tooth enamel.  The model will allow scientists to study how the disorder develops as well as to clarify the enamel-forming process.

Dr. Ashok Kulkarni and colleagues genetically engineered mice by deleting, or knocking out, the gene responsible for producing amelogenin, the most abundant protein in enamel.  As early as two weeks of age, the knockout mice had teeth with chalky white discoloration and an abnormally thin layer of enamel.  Detailed evaluation revealed that the enamel structure was atypical.  The scientists published their findings in the June 13 issue of the Journal of Biological Chemistry.

"This is the first animal model in which a tooth-specific gene has been knocked out," said the study's lead author Dr. Kulkarni from the NIDCR Functional Genomics Unit and Gene Targeting Facility.  "We think the mouse model will be useful for studying the functions of amelogenin in enamel formation as well as for developing therapies for amelogenesis imperfecta."

Amelogenesis imperfecta occurs in approximately 1 in 14,000 individuals in the U.S.  It results in malformed, thin enamel that may render teeth susceptible to damage and decay.  Dental enamel is the outermost layer of the teeth and is the hardest substance in the body.  It is composed of a protein framework  --  made up mostly of amelogenin  -- on which minerals such as calcium are deposited.

By analyzing the affected animals' teeth through a scanning electron microscope, the researchers found that the enamel lacked the classic "prism" pattern that is the hallmark of normal enamel crystal.  These findings revealed that the amelogenin protein is apparently not required for initiating enamel formation, since some enamel was present, but that it is necessary for the organization of the distinctive crystal pattern and the regulation of enamel thickness.

"This finding was unexpected," said Dr. Kulkarni.  "We thought the most likely scenario would be that the animals would have no tooth enamel at all since we knocked out the gene that produces amelogenin, the most plentiful enamel protein."  The small amount of enamel present was apparently composed of other cellular proteins, Dr. Kulkarni said.

Understanding the enamel-forming process could lead to replicating that process in the laboratory, the scientists say.  In the future, researchers may be able to use enamel produced in the laboratory to treat patients with amelogenesis imperfecta or those with missing or damaged enamel resulting from dental caries or trauma.

Collaborating with Dr. Kulkarni's group, which includes Drs. Bradford Hall, Glenn Longenecker, Tamizchelvi Thyagarajan, and Taduru Sreenath, were Drs. Carolyn Gibson, Zhi-An Yuan, Enhong Chen, Sylvia Decker, Ronald Piddington and Dr. Gerald Harrison from the University of Pennsylvania School of Dental Medicine; and Dr. J. Tim Wright from the University of North Carolina, Chapel Hill.

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