FGFR2b signaling regulates ex vivo submandibular gland epithelial cell proliferation and branching morphogenesis
FGFR2b signaling regulates ex vivo submandibular gland epithelial cell proliferation and branching morphogenesis
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DOI：
10.1242/dev.01690
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发表时间：
2005-03-01
期刊：
影响因子：
4.6
通讯作者：
Hoffman, MP
中科院分区：
文献类型：
--
作者：
Steinberg, Z;Myers, C;Hoffman, MP
小鼠颌下腺分支形态发生受多种生长因子的调控。在这里，我们报告了当FGFR2表达下调或可溶性重组FGFR2b竞争内源性生长因子时，完整颌下腺的体外分支减少。然而，抑制完整腺体中的分支需要FGF1、FGF7和FGF10的中和抗体组合，这表明分支需要多种FGF亚型。将外源性FGFs添加到没有间质培养的下颌上皮雏形中可诱导不同的形态。FGF7诱导上皮出芽，而FGF10诱导导管伸长，两者均被FGFR或ERK1/2信号抑制剂抑制。然而，pi3激酶抑制剂也会降低fgf7介导的上皮出芽，这表明存在多种信号通路。我们免疫定位了FGF受体，并分析了FGFR、FGF和MMP基因表达的变化，以确定FGF介导的形态发生机制。FGFR1b和FGFR2b存在于整个上皮中，尽管FGFR1b在芽周和导管尖端周围表达更高。与FGF10相比，FGF7信号通路增加FGFR1b和FGF1表达以及MMP2活性，导致细胞增殖和上皮芽扩张增加，而FGF10刺激导管尖端的局部增殖。FGF7-和fgf10介导的形态发生被MMP抑制剂和FGF1的中和抗体抑制，这表明FGF1和MMPs都是上皮形态发生的重要下游介质。综上所述，我们的数据表明，FGFR2b信号通路涉及FGFR1b/FGF1/MMP2表达的调控网络，该网络在分支形态发生过程中介导出芽和导管伸长。
Branching morphogenesis of mouse submandibular glands is regulated by multiple growth factors. Here, we report that ex vivo branching of intact submandibular glands decreases when either FGFR2 expression is downregulated or soluble recombinant FGFR2b competes out the endogenous growth factors. However, a combination of neutralizing antibodies to FGF1, FGF7 and FGF10 is required to inhibit branching in the intact gland, suggesting that multiple FGF isoforms are required for branching. Exogenous FGFs added to submandibular epithelial rudiments cultured without mesenchyme induce distinct morphologies. FGF7 induces epithelial budding, whereas FGF10 induces duct elongation, and both are inhibited by FGFR or ERK1/2 signaling inhibitors. However, a PI3-kinase inhibitor also decreases FGF7-mediated epithelial budding, suggesting that multiple signaling pathways exist. We immunolocalized FGF receptors and analyzed changes in FGFR, FGF and MMP gene expression to identify the mechanisms of FGF-mediated morphogenesis. FGFR1b and FGFR2b are present throughout the epithelium, although FGFR1b is more highly expressed around the periphery of the buds and the duct tips. FGF7 signaling increases FGFR1b and FGF1 expression, and MMP2 activity, when compared with FGF10, resulting in increased cell proliferation and expansion of the epithelial bud, whereas FGF10 stimulates localized proliferation at the tip of the duct. FGF7- and FGF10-mediated morphogenesis is inhibited by an MMP inhibitor and a neutralizing antibody to FGF1, suggesting that both FGF1 and MMPs are essential downstream mediators of epithelial morphogenesis. Taken together, our data suggests that FGFR2b signaling involves a regulatory network of FGFR1b/FGF1/MMP2 expression that mediates budding and duct elongation during branching morphogenesis.