Tissue geometry may govern lung branching mode selection.

Lung branching morphogenesis proceeds in three stereotyped modes (domain, planar, and orthogonal branching). Much is known about the molecular players, including growth factors such as fibroblast growth factor 10 but it is unknown how these signals could actuate the different branching patterns. With the aim of identifying mechanisms that may determine the different branching modes, we developed a computational model of the epithelial lung bud and its surrounding mesenchyme. We studied transport of morphogens and localization of morphogen flux at lobe surfaces and lobe edges. We find that a single simple mechanism is theoretically capable of directing an epithelial tubule to elongate, bend, flatten, or bifurcate, depending solely on geometric ratios of the tissues in the vicinity of a growing tubule tip. Furthermore, the same simple mechanism is capable of generating orthogonal or planar branching, depending only on the same geometric ratios.