Platelet-derived growth factor receptor regulates salivary gland morphogenesis via fibroblast growth factor expression.
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 beta-galactosidase-negative, indicating that most mesenchymal cells are derived from cranial neural crest cells. Platelet-derived growth factor (PDGF) receptor alpha 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, PDGFRalpha, and PDGFRbeta 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.
Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan.
Shinya
S
Yamamoto
Emiko
E
Fukumoto
Keigo
K
Yoshizaki
Tsutomu
T
Iwamoto
Aya
A
Yamada
Kojiro
K
Tanaka
Hiroharu
H
Suzuki
Shizuko
S
Aizawa
Makiko
M
Arakaki
Kenji
K
Yuasa
Kyoko
K
Oka
Yang
Y
Chai
Kazuaki
K
Nonaka
Satoshi
S
Fukumoto
D000818:Animals; D004847:Epithelial Cells / Q000166:cytology; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009024:Morphogenesis; D009432:Neural Crest / Q000378:metabolism; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D012469:Salivary Glands / Q000378:metabolism*; D015398:Signal Transduction
D034741:RNA, Small Interfering; D005346:Fibroblast Growth Factors; D017479:Receptors, Platelet-Derived Growth Factor