The characteristic structure of the mouse lung is largely formed through domain branching: the generation of new branches from the side of an existing branch. Now, Celeste Nelson and colleagues use ex vivo and in silico approaches to study the role of smooth muscle in domain branching. First, the authors observe that domain branches are stereotypically ensheathed by smooth muscle as they form. Next, the researchers use small molecules to promote or inhibit smooth muscle differentiation in lung explants. They find that reducing smooth muscle increases branching frequency, whereas increasing the amount of smooth muscle decreases the frequency of branch initiation and the rate at which the branch extends. Likewise, genetically ablating smooth muscle produces similar affects, but elimination of mature smooth muscle does not change epithelial morphology. Furthermore, the epithelium loses its branched structure when the surrounding mesenchyme is removed, indicating that smooth muscle holds the branches in shape. To investigate this further, the researchers construct a computational model, which supports the hypothesis that smooth muscle mechanically shapes the epithelium into branches. Taken together, these data indicate that the coordinated timing of smooth muscle differentiation during domain branching is necessary to ‘squeeze’ branches into shape.
