Fig. 8. Model for mesothelial-mesenchymal-epithelial regulation of pseudoglandular stage lung development. Molecular pathways mediating Fgf9 loss- and gain-of-function phenotypes (A) and spatial relationships between molecules (B-E). In wild-type tissue (C), FGF9 maintains proliferation and Fgf10 expression in sub-mesothelial mesenchyme (1) (see Figs 5, 7) (Colvin et al., 2001), and at early stages induces Shh in the epithelium and SHH signaling in the adjacent sub-epithelial mesenchyme (2) (Fig. 4). SHH signaling is necessary for sub-epithelial mesenchyme survival and proliferation, and limits Fgf10 expression primarily in the interbud regions (3) (Fig. 5) (Pepicelli et al., 1998), allowing focal sources of Fgf10 to induce epithelial branching (4) (Bellusci et al., 1997b; Park et al., 1998; Weaver et al., 2000). In the absence of Fgf9, Fgf10 expression is reduced such that epithelial branching arrests at E12.5 (B) (Colvin et al., 2001). When Fgf9 is overexpressed in airway epithelium at later stages (E12.5-E14.5) (D), Fgf10 expression is increased in sub-mesothelial mesenchyme (Fig. 7), but probably repressed in sub-epithelial mesenchyme through enhanced HH signaling (Fig. 4), facilitating tubule elongation, but not branching (2, 3). Fgf7 expression is increased in Fgf9 overexpressing lungs throughout sub-epithelial mesenchyme, inducing rapid epithelial luminal dilation (5) (Fig. 7). Cyclopamine mediated repression of SHH signaling (E) is suggested to de-represses Fgf10 in the sub-epithelial mesenchyme leading to increased budding (Fig. 6).