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Abstract
Genetic studies have shown that FGF10/FGFR2 signaling is required for airway branching morphogenesis and FGF10 functions as a chemoattractant factor for distal epithelial cells during lung development. However, the detail downstream cellular and molecular mechanisms have not been fully characterized. Using live imaging of ex vivo cultured lungs, we found that tip airway epithelial progenitor cells migrate faster than cleft cells during airway bud formation and this migration process is controlled by FGFR2-mediated ERK1/2 signaling. Additionally, we found that airway progenitor cells that migrate faster tend to become distal airway progenitor cells. We identified that Anxa4 is a downstream target of ERK1/2 signaling. Anxa4−/− airway epithelial cells exhibit a “lag-behind” behavior and tend to stay at the stalk airways. Moreover, we found that Anxa4-overexpressing cells tend to migrate to the bud tips. Finally, we demonstrated that Anxa4 functions redundantly with Anxa1 and Anxa6 in regulating endoderm budding process. Our study demonstrates that ERK1/2/Anxa4 signaling plays a role in promoting the migration of airway epithelial progenitor cells to distal airway tips and ensuring their distal cell fate.
Highlights
The airways of mammalian lungs are generated via a process called branching morphogenesis
Airway progenitor cells that migrate faster tend to commit to distal airway cell fate
We investigated the effect of loss of Fgfr[2] on airway epithelial cell fate determination
Summary
The airways of mammalian lungs are generated via a process called branching morphogenesis. FGF10 has been shown to induce lung endoderm bud expansion and budding in mesenchyme-free lung endoderm explant cultures[6,7] It has been shown in vitro that FGF10 acts as a chemoattractant factor for distal airway epithelium[8,9]. These findings have established an essential role of FGF10 in regulating the directional outgrowth of airway buds during branching morphogenesis. It has been showed that FGF10 signaling is essential for preventing distal airway progenitor cell from differentiating into stalk airway epithelial cell[20,21]. Despite the abundance and conservation of Annexins in most eukaryotic species, relatively little is known about the regulation of Annexin gene expression and little is known about the function of Annexin proteins during embryonic lung development
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