Figure 5.

Proposed model of mesenchymal barriers to epithelial growth resulting in bifurcation. A combination of localized fibronectin and airway smooth muscle (ASM) expression forms a physical barrier to expanding branches, resulting in tip cleft formation and bifurcation. ASM partly derives from Fgf10 expressing progenitors, which are regulated upstream by Fgf9, and downstream by Shh. Fibronectin deposition is regulated by Dkk1/Wnt signaling downstream of Fgfr2b, and upregulates the expression of Btbd7 in the cleft. Anxa4 marks tip progenitor cells, and is involved in cell migratory behavior. Dark and light blue ovals represent localized sources of high and low Fgf10 expression, respectively.