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J. Biol. Chem., Vol. 283, Issue 8, 4825-4833, February 22, 2008

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Transcription Factor Epiprofin Is Essential for Tooth Morphogenesis by Regulating Epithelial Cell Fate and Tooth Number^*

Takashi Nakamura, Susana de Vega¹, Satoshi Fukumoto, Lucia Jimenez^¶2, Fernando Unda^¶, and Yoshihiko Yamada³

From the Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, the Department of Pediatric Dentistry, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan, and the ^¶Department of Cell Biology and Histology, Faculty of Medicine and Dentistry, University of the Basque Country, 48940 Vizcaya, Spain

In tooth morphogenesis, the dental epithelium and mesenchyme interact reciprocally for growth and differentiation to form the proper number and shapes of teeth. We previously identified epiprofin (Epfn), a gene preferentially expressed in dental epithelia, differentiated ameloblasts, and certain ectodermal organs. To identify the role of Epfn in tooth development, we created Epfn-deficient mice (Epfn^-/-). Epfn^-/- mice developed an excess number of teeth, enamel deficiency, defects in cusp and root formation, and abnormal dentin structure. Mutant tooth germs formed multiple dental epithelial buds into the mesenchyme. In Epfn^-/- molars, rapid proliferation and differentiation of the inner dental epithelium were inhibited, and the dental epithelium retained the progenitor phenotype. Formation of the enamel knot, a signaling center for cusps, whose cells differentiate from the dental epithelium, was also inhibited. However, multiple premature nonproliferating enamel knot-like structures were formed ectopically. These dental epithelial abnormalities were accompanied by dysregulation of Lef-1, which is required for the normal transition from the bud to cap stage. Transfection of an Epfn vector promoted dental epithelial cell differentiation into ameloblasts and activated promoter activity of the enamel matrix ameloblastin gene. Our results suggest that in Epfn-deficient teeth, ectopic nonproliferating regions likely bud off from the self-renewable dental epithelium, form multiple branches, and eventually develop into supernumerary teeth. Thus, Epfn has multiple functions for cell fate determination of the dental epithelium by regulating both proliferation and differentiation, preventing continuous tooth budding and generation.

Received for publication, October 9, 2007 , and in revised form, December 19, 2007.

^* This work was supported by grants from the Intramural Research Program of the NIDCR, National Institutes of Health (to Y. Y.), grants-in-aid for Research Fellows of the Japan Society for the Promotion of Science from the Ministry of Education, Science and Culture of Japan (Grant 15689025 and 17689058 to S. F.), and the University of the Basque Country (Grant IU05/27, to F. U.). 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 Supported by a fellowship of the Basque Government, Spain.

² Supported by a fellowship of the University of the Basque Country.

³ To whom correspondence should be addressed: Bldg. 30, Rm. 407, NIDCR, National Institutes of Health, 30 Convent Dr., MSC 4370, Bethesda, MD 20892-4370. Tel.: 301-496-2111; Fax: 301-402-0897; E-mail: yoshi.yamada{at}nih.gov.

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