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J. Biol. Chem., Vol. 283, Issue 6, 3385-3391, February 8, 2008

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Neurotrophic Factor Neurotrophin-4 Regulates Ameloblastin Expression via Full-length TrkB^*

Keigo Yoshizaki, Shinya Yamamoto, Aya Yamada, Kenji Yuasa, Tsutomu Iwamoto, Emiko Fukumoto^¶, Hidemitsu Harada^||, Masahiro Saito^**, Akihiko Nakasima, Kazuaki Nonaka, Yoshihiko Yamada, and Satoshi Fukumoto¹

From the Section of Pediatric Dentistry and Orthodontics, Division of Oral Health, Growth, and Development, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan, ^¶Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8521, Japan, the ^||Department of Oral Anatomy II, Iwate Medical College School of Dentistry, Morioka, Iwate 020-8505, Japan, the ^**Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871, Japan, the Craniofacial Developmental Biology and Regeneration Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, and the Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai, Miyagi 980-8575, Japan

Neurotrophic factors play an important role in the development and maintenance of not only neural but also nonneural tissues. Several neurotrophic factors are expressed in dental tissues, but their role in tooth development is not clear. Here, we report that neurotrophic factor neurotrophin (NT)-4 promotes differentiation of dental epithelial cells and enhances the expression of enamel matrix genes. Dental epithelial cells from 3-day-old mice expressed NT-4 and three variants of TrkB receptors for neurotrophins (full-length TrkB-FL and truncated TrkB-T1 and -T2). Dental epithelial cell line HAT-7 expressed these genes, similar to those in dental epithelial cells. We found that NT-4 reduced HAT-7 cell proliferation and induced the expression of enamel matrix genes, such as ameloblastin (Ambn). Transfection of HAT-7 cells with the TrkB-FL expression construct enhanced the NT-4-mediated induction of Ambn expression. This enhancement was blocked by K252a, an inhibitor for Trk tyrosine kinases. Phosphorylation of ERK1/2, a downstream molecule of TrkB, was induced in HAT-7 cells upon NT-4 treatment. TrkB-FL but not TrkB-T1 transfection increased the phosphorylation level of ERK1/2 in NT-4-treated HAT-7 cells. These results suggest that NT-4 induced Ambn expression via the TrkB-MAPK pathway. The p75 inhibitor TAT-pep5 decreased NT-4-mediated induction of the expression of Ambn, TrkB-FL, and TrkB-T1, suggesting that both high affinity and low affinity neurotrophin receptors were required for NT-4 activity. We found that NT-4-null mice developed a thin enamel layer and had a decrease in Ambn expression. Our results suggest that NT-4 regulates proliferation and differentiation of the dental epithelium and promotes production of the enamel matrix.

Received for publication, June 14, 2007 , and in revised form, October 31, 2007.

^* This work was supported in part by Grants-in-aid for Research Fellows 15689025, 17689058, 19791585, and 17659650 from the Japan Society for the Promotion of Science and the Ministry of Education, Science, and Culture of Japan (to S. F., A. Y., and K. N.). 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 supplemental Table 1 and Figs. 1–3.

¹ To whom correspondence should be addressed: Division of Pediatric Dentistry, Dept. of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai, Miyagi 980-8575, Japan. Fax: 81-22-717-8380; E-mail: fukumoto{at}mail.tains.tohoku.ac.jp.

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