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J. Biol. Chem., Vol. 281, Issue 8, 5008-5016, February 24, 2006

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Laminin 5 Is Required for Dental Epithelium Growth and Polarity and the Development of Tooth Bud and Shape^*

Satoshi Fukumoto¹, Jeffrey H. Miner, Hiroko Ida², Emiko Fukumoto^¶, Kenji Yuasa^||, Hiroshi Miyazaki^**, Matthew P. Hoffman, and Yoshihiko Yamada³

From the Craniofacial Developmental Biology and Regeneration Branch and ^**Oral and Pharyngeal Cancer Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, the Renal Division, Washington University School of Medicine, St. Louis, Missouri 63110, the ^¶Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8521, Japan, and the ^||Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan

In tooth development, the oral ectoderm and mesenchyme coordinately and reciprocally interact through the basement membrane for their growth and differentiation to form the proper shape and size of the tooth. Laminin 5 subunit-containing laminin-10/11 (LM-511/521) is the major laminin in the tooth germ basement membrane. Here, we have examined the role of laminin 5 (Lama5) in tooth development using laminin 5-null mouse primary dental epithelium and tooth germ organ cultures. Lama5-null mice develop a small tooth germ with defective cusp formation and have reduced proliferation of dental epithelium. Also, cell polarity and formation of the monolayer of the inner dental epithelium are disturbed. The enamel knot, a signaling center for tooth germ development, is defective, and there is a significant reduction of Shh and Fgf4 expression in the dental epithelium. In the absence of laminin 5, the basement membrane in the inner dental epithelium becomes discontinuous. In normal mice, integrin 64, a receptor for laminin 5, is strongly localized at the basal layer of the epithelium, whereas in mutant mice, integrin 64 is expressed around the cell surface. In primary dental epithelium culture, laminin-10/11 promotes cell growth, spreading, and filopodia-like microspike formation. This promotion is inhibited by anti-integrin 6 and 4 antibodies and by phosphatidylinositol 3-kinase inhibitors and dominant negative Rho-GTPase family proteins Cdc42 and Rac. In organ culture, anti-integrin 6 antibody and wortmannin reduce tooth germ size and shape. Our studies demonstrate that laminin 5 is required for the proliferation and polarity of basal epithelial cells and suggest that the interaction between laminin-10/11-integrin 64 and the phosphatidylinositol 3-kinase-Cdc42/Rac pathways play an important role in determining the size and shape of tooth germ.

Received for publication, August 23, 2005 , and in revised form, November 29, 2005.

^* This work was supported by the intramural research program of the NIDCR, National Institutes of Health, and 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. 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 online version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Present address: Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan.

² Present address: Faculty of Dentistry, Niigata University, Niigata 940-0061, Japan.

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

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