Figure 7.

Relationship of the vasculature, nerves, and airway systems during branching morphogenesis. (A) The development of branching airway epithelium (green) is tightly coordinated with vascularization (brown) and depends on nerves (orange) innervating surrounding airway smooth muscle (ASM). (B) A simplified airway epithelial cell is illustrated to show the role of Fgf10 signaling on vasculogenesis and angiogenesis in the adjacent mesenchyme. Fgf10/Spry2 signaling promotes Vegf-a expression via mTORC1-HIF-1α. See text for details. (C) Nerves not only innervate ASM, but neuroendocrine (NE) cells and neuroepithelial bodies (NEB) as well. These rare cells have been implicated in the branching process, though little is known about the underlying mechanisms. ASM progenitors (red) guide axonal growth toward regions of ASM formation by releasing Bdnf. Bdnf is downregulated by miR-206, which is itself downregulated by Shh secreted from the epithelium. We speculate that this regulatory axis lies downstream of Fgf10 signaling.