Research ArticleDevelopment

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

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Science Signaling  03 Mar 2020:
Vol. 13, Issue 621, eaay4353
DOI: 10.1126/scisignal.aay4353

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Differential FGF signaling in the same tissue

Fibroblast growth factors (FGFs) stimulate various intracellular signaling pathways through a limited number of receptors (FGFRs). Yin and Ornitz found that activation of distinct FGFRs by FGF9 and FGF10 preferentially activated distinct intracellular signaling pathways in the embryonic mouse lung epithelium, resulting in different developmental effects. Whereas FGF9 promoted distal epithelial fate specification and inhibited epithelial differentiation, FGF10 promoted epithelial proliferation and differentiation. Mechanistically, FGF9 activated phosphoinositide 3-kinase (PI3K) signaling through FGFR3, whereas FGF10 activated mitogen-activated protein kinase (MAPK) signaling through FGFR2b. Thus, two different FGFRs can function in the same cell type and transmit distinct signals with distinct phenotypic outcomes.

Abstract

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.

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