Platelet-derived growth factor receptor regulates salivary gland morphogenesis via fibroblast growth factor expression

血小板源性生长因子受体通过成纤维细胞生长因子表达调节唾液腺形态发生

• 批准号: 21792089
• 负责人: YAMAMOTO Shinya
• 金额: $ 2.75万
• 依托单位: Kagoshima University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21792089/
• 关键词: 発生・分化; 器官培養; マウス顎下腺; 増殖因子; シグナル伝達; PDGF; 分岐形態形成; 細胞増殖

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.

上皮细胞和间充质细胞之间的相互作用参与了唾液腺的形态发生。Wnt 1-Cre/R26 R小鼠的颌下腺（SMG）显示间充质阳性，而上皮细胞为β-半乳糖苷酶阴性，表明大多数间充质细胞来源于颅神经嵴细胞。血小板衍生生长因子（PDGF）受体α是神经嵴衍生细胞的标志物之一。在这项研究中，我们分析了PDGFs及其受体在小鼠SMGs形态发生中的作用。PDGF-A显示在SMG上皮中表达，而PDGF-B、PDGFR α和PDGFR β在间充质中表达。外源性PDGF-AA和-BB在SMG器官培养物中表现出增加的分支和上皮细胞增殖水平，尽管它们的受体被发现在间充质中表达。相比之下，短干扰RNA的Pdgfa和-B以及中和抗体的PDGF-AB和-BB显示减少分支。PDGF-AA诱导成纤维细胞生长因子基因Fgf 3和-7的表达，PDGF-BB诱导Fgf 1、-3、-7和-10的表达，而Pdgfa和Pdgfb的短干扰RNA抑制Fgf 3、-7和-10的表达，表明PDGFs调节SMG间充质中Fgf基因的表达。PDGF受体抑制剂AG-17抑制PDGF诱导的分支，而外源性FGF 7和-10完全恢复。总之，这些结果表明成纤维细胞生长因子在PDGF信号传导的下游起作用，PDGF信号传导调节神经嵴来源的间充质细胞和SMG分支形态发生中的Fgf表达。因此，PDGF信号传导是参与上皮和神经嵴源性间充质之间相互作用的可能机制。

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• DOI: 10.1016/j.archoralbio.2010.03.011
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