Fig. 7. Summary of paracrine interactions shaping the Foxf1 expression pattern in developing lung. (A) Activation of Foxf1 by Shh is based on both ectopic expression and loss-of-function experiments presented in this work. The inclusion of Gli2/3 in this pathway is inferred from their role in transducing the hedgehog signal and the similarity between Gli2/3 knockout phenotypes and the Foxf1 heterozygote phenotype. Inhibition by BMP4 refers to the effect of BMP4 beads on Foxf1 expression presented here. The role of FGF10 and FGF7 in regulation of Bmp4 and Shh, respectively, has been published by others (Lebeche et al., 1999) and has also been confirmed by us; the net effect of FGFs on Foxf1 expression was analyzed in this work. (B) High magnification view of lung explant hybridized with a Foxf1 probe. Foxf1 expression in subepithelial mesenchyme peaks at the transition between the proximal, tubular epithelium the distal, bulbous part of the bud. The circular object is a bead implanted in the mesenchyme as a negative control and has no relevance for the expression pattern discussed here. (C) Model of paracrine signaling in a lung bud that provides a possible explanation for the observed distribution of Foxf1 mRNA. Proximal tubular epithelium secretes a low level of Shh (pink), which gives rise to a low level of Foxf1 expression (light blue) in the subepithelial mesenchyme. Shh secretion is higher in the distal epithelium (red), which activates high level expression of Foxf1 (dark blue). Fgf10 is expressed in mesenchyme at the distal tip of the bud (black). In response to FGF10 signaling, Bmp4 is activated in the most distal epithelium (green). Secretion of BMP4 inhibits Foxf1 expression, which therefore drops again towards the tip of the bud (light blue).
