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J. Biol. Chem., Vol. 283, Issue 34, 23139-23149, August 22, 2008

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Platelet-derived Growth Factor Receptor Regulates Salivary Gland Morphogenesis via Fibroblast Growth Factor Expression^*

Shinya Yamamoto, Emiko Fukumoto, Keigo Yoshizaki, Tsutomu Iwamoto, Aya Yamada^¶, Kojiro Tanaka^¶, Hiroharu Suzuki^¶, Shizuko Aizawa^¶, Makiko Arakaki^¶, Kenji Yuasa, Kyoko Oka, Yang Chai^||, Kazuaki Nonaka, and Satoshi Fukumoto^¶1

From the Section of Pediatric Dentistry, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan, Division of Preventive Dentistry, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan, ^||Center for Craniofacial Molecular Biology, School of Dentistry University of Southern California, Los Angeles, California 90033, and ^¶Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan

A coordinated reciprocal interaction between epithelium and mesenchyme is involved in salivary gland morphogenesis. The submandibular glands (SMGs) of Wnt1-Cre/R26R mice have been shown positive for mesenchyme, whereas the epithelium is β-galactosidase-negative, indicating that most mesenchymal cells are derived from cranial neural crest cells. Platelet-derived growth factor (PDGF) receptor is one of the markers of neural crest-derived cells. In this study, we analyzed the roles of PDGFs and their receptors in the morphogenesis of mouse SMGs. PDGF-A was shown to be expressed in SMG epithelium, whereas PDGF-B, PDGFR, and PDGFRβ were expressed in mesenchyme. Exogenous PDGF-AA and -BB in SMG organ cultures demonstrated increased levels of branching and epithelial proliferation, although their receptors were found to be expressed in mesenchyme. In contrast, short interfering RNA for Pdgfa and -b as well as neutralizing antibodies for PDGF-AB and -BB showed decreased branching. PDGF-AA induced the expression of the fibroblast growth factor genes Fgf3 and -7, and PDGF-BB induced the expression of Fgf1, -3, -7, and -10, whereas short interfering RNA for Pdgfa and Pdgfb inhibited the expression of Fgf3, -7, and -10, indicating that PDGFs regulate Fgf gene expression in SMG mesenchyme. The PDGF receptor inhibitor AG-17 inhibited PDGF-induced branching, whereas exogenous FGF7 and -10 fully recovered. Together, these results indicate that fibroblast growth factors function downstream of PDGF signaling, which regulates Fgf expression in neural crest-derived mesenchymal cells and SMG branching morphogenesis. Thus, PDGF signaling is a possible mechanism involved in the interaction between epithelial and neural crest-derived mesenchyme.

Received for publication, December 19, 2007 , and in revised form, June 6, 2008.

^* This work was supported in part by 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 15689025 and 17689058 (to S. F.). 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 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 980-8575, Japan. Fax: 81-22-717-8386; E-mail: fukumoto{at}mail.tains.tohoku.ac.jp.

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