Lung hypoplasia and neonatal death in Fgf9-null mice identify this gene asan essential regulator of lung mesenchyme

Mammalian lung develops as an evagination of ventral gut endoderm into the underlying mesenchyme. iterative epithelial branching, regulated by the sur rounding mesenchyme, generates an elaborate network of airways from the ini tial lung bud. Fibroblast growth factors (FGFs) often mediate epithelial-me senchymal interactions and mesenchymal Fgf10 is essential for epithelial br anching in the developing lung. However, no FGF has been shown to regulate lung mesenchyme. In embryonic lung, Fgf9 is detected in airway epithelium a nd visceral pleura at E10.5, but is restricted to the pleura by E12.5. We r eport that mice homozygous for a targeted disruption of Fgf9 exhibit lung h ypoplasia and early postnatal death. Fgf9(-/-) lungs exhibit reduced mesenc hyme and decreased branching of airways, but show significant distal airspa ce formation and pneumocyte differentiation. Our results suggest that Fgf9 affects lung size by stimulating mesenchymal proliferation. The reduction i n the amount of mesenchyme in Fgf9(-/-) lungs limits expression of mesenchy mal Fgf10. We suggest a model whereby FGF9 signaling from the epithelium an d reciprocal FGF10 signaling from the mesenchyme coordinately regulate epit helial airway branching and organ size during lung embryogenesis.