FGF9 and FGF10 use distinct signaling pathways to direct lung epithelial specification and branching

Fibroblast Growth Factors (FGFs) 9 and 10 are essential during the pseudoglandular stage of lung development. Mesothelial produced FGF9 is principally responsible for mesenchymal growth, whereas epithelial produced FGF9 and mesenchymal 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 mechanisms. Here, we show that FGF9 signaled through epithelial FGF receptor 3 (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 PI3K pathways, whereas FGFR2b relied on downstream RAS-MAPK pathways. These data demonstrate that within lung epithelial cells, different FGFRs function independently; they bind receptor-specific ligands and direct unique developmental functions through activation of distinct downstream signaling pathways.