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J. Biol. Chem., Vol. 283, Issue 16, 10858-10871, April 18, 2008

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Enamel Defects and Ameloblast-specific Expression in Enam Knock-out/lacZ Knock-in Mice^*

Jan C.-C. Hu¹, Yuanyuan Hu, Charles E. Smith^¶, Marc D. McKee^||, J. Timothy Wright^**, Yasuo Yamakoshi, Petros Papagerakis, Graeme K. Hunter, Jerry Q. Feng, Fumiko Yamakoshi, and James P. Simmer

From the Department of Orthodontics and Pediatric Dentistry and Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan 48108, ^¶Laboratory for the Study of Calcified Tissues and Biomaterials, Faculté de Médecine Dentaire, Université de Montréal, Montreal, Quebec H3C 3J7, Canada, ^||Department of Anatomy and Cell Biology, Jamson T. N. Wong Laboratories for Calcified Tissue Research, McGill Centre for Bone and Peridodontal Research, and the Fonds de la Recherche en Santé du Québec (FRSQ) Network for Oral and Bone Health Research, McGill University, Faculty of Dentistry, Montreal, Quebec H3A 2B2, Canada, ^**Department of Pediatric Dentistry, University of North Carolina, Chapel Hill, North Carolina 27599-7455, Canadian Institutes of Health Research Group in Skeletal Development and Remodeling, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada, and Department of Biomedical Sciences, Baylor College of Dentistry, Dallas, Texas 75246

Enamelin is critical for proper dental enamel formation, and defects in the human enamelin gene cause autosomal dominant amelogenesis imperfecta. We used gene targeting to generate a knock-in mouse carrying a null allele of enamelin (Enam) that has a lacZ reporter gene replacing the Enam translation initiation site and gene sequences through exon 7. Correct targeting of the transgene was confirmed by Southern blotting and PCR analyses. No enamelin protein could be detected by Western blotting in the Enam-null mice. Histochemical 5-bromo-4-chloro-3-indolyl-β-D-galactopyranoside (X-gal) staining demonstrated ameloblast-specific expression of enamelin. The enamel of the Enam^+/- mice was nearly normal in the maxillary incisors, but the mandibular incisors were discolored and tended to wear rapidly where they contacted the maxillary incisors. The Enam^-/- mice showed no true enamel. Radiography, microcomputed tomography, and light and scanning electron microscopy were used to document changes in the enamel of Enam^-/- mice but did not discern any perturbations of bone, dentin, or any other tissue besides the enamel layer. Although a thick layer of enamel proteins covered normal-appearing dentin of unerupted teeth, von Kossa staining revealed almost a complete absence of mineral formation in this protein layer. However, a thin, highly irregular, mineralized crust covered the dentin on erupted teeth, apparently arising from the formation and fusion of small mineralization foci (calcospherites) in the deeper part of the accumulated enamel protein layer. These results demonstrate ameloblast-specific expression of enamelin and reveal that enamelin is essential for proper enamel matrix organization and mineralization.

Received for publication, December 28, 2007 , and in revised form, February 4, 2008.

^* This study was supported by NIDCR/National Institutes of Health Grant Project DE 11301. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental table.

¹ To whom correspondence should be addressed: University of Michigan Dental Research Lab., 1210 Eisenhower Pl., Ann Arbor, MI 48108. Tel.: 734-975-9315; Fax: 734-975-9326; E-mail: janhu{at}umich.edu.

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