title: Enamelin is critical for ameloblast integrity and enamel ultrastructure formation.
abstract: Mutations in the human enamelin gene cause autosomal dominant hypoplastic amelogenesis imperfecta in which the affected enamel is thin or absent. Study of enamelin knockout NLS-lacZ knockin mice revealed that mineralization along the distal membrane of ameloblast is deficient, resulting in no true enamel formation. To determine the function of enamelin during enamel formation, we characterized the developing teeth of the Enam-/- mice, generated amelogenin-driven enamelin transgenic mouse models, and then introduced enamelin transgenes into the Enam-/- mice to rescue enamel defects. Mice at specific stages of development were subjected to morphologic and structural analysis using β-galactosidase staining, immunohistochemistry, and transmission and scanning electron microscopy. Enamelin expression was ameloblast-specific. In the absence of enamelin, ameloblasts pathology became evident at the onset of the secretory stage. Although the aggregated ameloblasts generated matrix-containing amelogenin, they were not able to create a well-defined enamel space or produce normal enamel crystals. When enamelin is present at half of the normal quantity, enamel was thinner with enamel rods not as tightly arranged as in wild type suggesting that a specific quantity of enamelin is critical for normal enamel formation. Enamelin dosage effect was further demonstrated in transgenic mouse lines over expressing enamelin. Introducing enamelin transgene at various expression levels into the Enam-/- background did not fully recover enamel formation while a medium expresser in the Enam+/- background did. Too much or too little enamelin abolishes the production of enamel crystals and prism structure. Enamelin is essential for ameloblast integrity and enamel formation.
authors.affiliation: Dental Research Laboratory, University of Michigan School of Dentistry, Ann Arbor, Michigan, United States of America.
authors.forename: Jan C-C
authors.initials: JC
authors.lastname: Hu
authors.affiliation: Dental Research Laboratory, University of Michigan School of Dentistry, Ann Arbor, Michigan, United States of America.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Dental Research Laboratory, University of Michigan School of Dentistry, Ann Arbor, Michigan, United States of America.
authors.forename: Yuhe
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Dental Research Laboratory, University of Michigan School of Dentistry, Ann Arbor, Michigan, United States of America; Facility for Electron Microscopy Research, Department of Anatomy and Cell Biology, and Faculty of Dentistry, McGill University, Montreal, QC, Canada.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Smith
authors.affiliation: Dental Research Laboratory, University of Michigan School of Dentistry, Ann Arbor, Michigan, United States of America.
authors.forename: Rangsiyakorn
authors.initials: R
authors.lastname: Lertlam
authors.affiliation: Dental Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: John Timothy
authors.initials: JT
authors.lastname: Wright
authors.affiliation: Dental Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Suggs
authors.affiliation: McGill University, Faculty of Dentistry, and Department of Anatomy and Cell Biology, Montreal, QC, Canada.
authors.forename: Marc D
authors.initials: MD
authors.lastname: McKee
authors.affiliation: Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Elia
authors.initials: E
authors.lastname: Beniash
authors.affiliation: Dental Research Laboratory, University of Michigan School of Dentistry, Ann Arbor, Michigan, United States of America.
authors.forename: M Enamul
authors.initials: ME
authors.lastname: Kabir
authors.affiliation: Dental Research Laboratory, University of Michigan School of Dentistry, Ann Arbor, Michigan, United States of America.
authors.forename: James P
authors.initials: JP
authors.lastname: Simmer
mesh_terms: D000565:Ameloblasts / Q000378:metabolism*; D053523:Amelogenin / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D000831:Animals, Newborn; D003743:Dental Enamel / Q000196:embryology / Q000378:metabolism* / Q000648:ultrastructure; D003746:Dental Enamel Proteins / Q000235:genetics / Q000378:metabolism*; D003804:Dentin / Q000196:embryology / Q000378:metabolism / Q000648:ultrastructure; D007150:Immunohistochemistry; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D008963:Molar / Q000196:embryology / Q000378:metabolism; D013194:Staining and Labeling / Q000379:methods; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D053523:Amelogenin; D003746:Dental Enamel Proteins; C038456:tuftelin; D001616:beta-Galactosidase