Fibroblast growth factors (FGFs) 9 and 10 are essential during the pseudoglandular stage of lung development. Mesothelium-produced FGF9 is principally responsible for mesenchymal growth, whereas epithelium-produced FGF9 and mesenchyme-produced FGF10 guide lung epithelial development, and loss of either of these ligands affects epithelial branching. Because FGF9 and FGF10 activate distinct FGF receptors (FGFRs), we hypothesized that they would control distinct developmental processes. Here, we found that FGF9 signaled through epithelial FGFR3 to directly promote distal epithelial fate specification and inhibit epithelial differentiation. By contrast, FGF10 signaled through epithelial FGFR2b to promote epithelial proliferation and differentiation. Furthermore, FGF9-FGFR3 signaling functionally opposed FGF10-FGFR2b signaling, and FGFR3 preferentially used downstream phosphoinositide 3-kinase (PI3K) pathways, whereas FGFR2b relied on downstream mitogen-activated protein kinase (MAPK) pathways. These data demonstrate that, within lung epithelial cells, different FGFRs function independently; they bind receptor-specific ligands and direct distinct developmental functions through the activation of distinct downstream signaling pathways.

中文翻译：

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FGF9 和 FGF10 激活不同的信号通路来指导肺上皮的规范和分支。


成纤维细胞生长因子 (FGF) 9 和 10 在肺发育的假腺体阶段至关重要。间皮产生的 FGF9 主要负责间充质生长，而上皮产生的 FGF9 和间充质产生的 FGF10 引导肺上皮发育，并且这些配体中任何一个的丢失都会影响上皮分支。由于 FGF9 和 FGF10 激活不同的 FGF 受体 (FGFR)，因此我们假设它们会控制不同的发育过程。在这里，我们发现 FGF9 通过上皮 FGFR3 发出信号，直接促进远端上皮命运规范并抑制上皮分化。相比之下，FGF10 通过上皮 FGFR2b 发出信号，促进上皮增殖和分化。此外，FGF9-FGFR3 信号传导在功能上与 FGF10-FGFR2b 信号传导相反，FGFR3 优先使用下游磷酸肌醇 3-激酶 (PI3K) 途径，而 FGFR2b 依赖下游丝裂原激活蛋白激酶 (MAPK) 途径。这些数据表明，在肺上皮细胞内，不同的 FGFR 独立发挥作用；它们结合受体特异性配体，并通过激活不同的下游信号通路来指导不同的发育功能。