Smooth muscle differentiation physically sculpts domain branches during mouse lung development

During branching morphogenesis, an epithelial tube is physically guided by the surrounding mesenchyme to proliferate and branch to generate an arborized network. In the mouse lung, the overall architecture is established by domain branching off of an existing branch, while bifurcations build a space-filling network. The developing airways are gradually encircled with smooth muscle derived from the mesenchyme, and specific spatial patterns of smooth muscle are required for bifurcation. Here, we examined smooth muscle differentiation during domain branching. We found that changes in morphology of domain branches are stereotyped, and are accompanied by an increase in smooth muscle wrapping at the base of the new branch. Perturbing the pattern of smooth muscle differentiation results in abnormal branch positioning and morphology. Loss of smooth muscle causes ectopic branching events and slows branch thinning, whereas enhanced smooth muscle differentiation suppresses branch initiation and extension. Our work shows that smooth muscle physically sculpts domain branches during mouse lung morphogenesis.