Fig. 6. Models for molecular signaling in developing lung. (A) Reciprocal FGF signaling between epithelium and mesenchyme during lung (top) and limb (bottom) embryogenesis. (A, top) We propose that FGF9 from the lung epithelium and pleura activates FGFR1c in the mesenchyme, while FGF10 from the mesenchyme activates FGFR2b in the epithelium. (A, bottom) Similar essential reciprocal epithelial-mesenchymal signaling between FGF10 in the mesenchyme and FGF8 in the overlying apical ectodermal ridge (AER) regulates limb bud outgrowth in mouse embryos. (DM, distal mesenchyme; ZPA, zone of polarizing activity). (FGF8 and FGF9 may also signal through FGFR2c, but Fgfr1 is more highly expressed than Fgfr2 in embryonic lung and limb mesenchyme (Peters et al., 1992).) (B) Model for interactions between Fgf and non-Fgf signaling pathways in developing lung. (B, top) Signaling during proximal airway branching in the early pseudoglandular period. (1) FGF9 (blue) in both airway epithelium and pleura stimulates mesenchymal proliferation. (Grey shading indicates mesenchyme.) (2) FGF10 (red) in the mesenchyme induces airway branching by stimulating endoderm proliferation and migration. (3) SHH (hatched) in the airway epithelium promotes mesenchymal proliferation. (B, middle) Signaling during airway branching in the late pseudoglandular period. (1) FGF9, now limited to the pleura, stimulates mesenchymal proliferation. (2) Mesenchymal FGF10 stimulates endoderm proliferation and migration, and appears to induce distal epithelial BMP4 expression (yellow). (3) BMP4 appears to inhibit airway branching by inhibiting endoderm proliferation, and perhaps by inhibiting endoderm migration. (4) SHH in the epithelium stimulates mesenchymal proliferation. Vascular defects in Shh-/- lungs indicate that Shh regulates development of mesenchymal vasculature. SHH also appears to prevent more generalized mesenchymal expression of Fgf10 (truncated symbol). (B, bottom) Signaling during development of distal airspaces. Mesenchyme surrounding epithelial buds is sharply reduced; focally high Fgf10 expression in the adjacent mesenchyme is lost; and epithelial differentiation begins with the narrowing of the epithelium. (1) Epithelial Bmp4 expression is essential for distal epithelial differentiation. (2) Continued Shh expression in the epithelium may regulate vascular development. In this model, distal lung development proceeds when mesenchyme surrounding developing airways thins, Fgf10 expression is reduced and Bmp4 expression is high. In Fgf9-/- lungs, loss of Fgf9-induced mesenchymal proliferation could result in premature reduction in mesenchyme surrounding budding airways, leading to premature reduction in Fgf10 expression. This would allow distal lung development to commence after fewer iterations of airway branching.
