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SummarySmooth muscle differentiation has been proposed to sculpt airway epithelial branches in mammalian lungs. Serum response factor (SRF) acts with its cofactor myocardin to promote the expression of contractile smooth muscle markers. However, smooth muscle cells exhibit a variety of phenotypes beyond contractile that are independent of SRF/myocardin-induced transcription. To determine whether airway smooth muscle exhibits phenotypic plasticity during embryonic development, we deleted Srf from the pulmonary mesenchyme. Srf-mutant lungs branch normally, and the mesenchyme exhibits normal cytoskeletal features and patterning. scRNA-seq revealed an Srf-null smooth muscle cluster wrapping the airways of mutant lungs that lacks contractile smooth muscle markers but retains many features of control smooth muscle. Srf-null airway smooth muscle exhibits a synthetic phenotype, compared to the contractile phenotype of mature wildtype airway smooth muscle. Our findings reveal plasticity in airway smooth muscle differentiation and demonstrate that a synthetic smooth muscle layer is sufficient for airway branching morphogenesis.

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SummaryEvolution has generated a beautiful diversity of epithelial architectures in the lungs of terrestrial vertebrates, from the tree-like lungs of mammals, to the sac-like lungs of reptiles, to the looped airways of birds. The physical mechanisms that generate pulmonary epithelia of such different shapes are just beginning to be uncovered. Pulmonary smooth muscle plays stage-dependent roles in shaping the epithelium during lung development in the mouse, anole, and chicken. We hypothesized that differences in the timing and spatial patterns of smooth muscle differentiation correspond to distinct patterns of gene expression in the pulmonary mesenchyme. To test this hypothesis and investigate differences in pulmonary smooth muscle patterning across terrestrial vertebrates, we generated scRNA-seq datasets from lungs of mouse, anole, and chicken embryos. These data revealed that smooth muscle regulators are expressed in similar patterns in mouse and anole lungs, in which epithelial branches are sculpted by smooth muscle, but diverge in chicken lungs, in which the epithelium branches in the absence of smooth muscle. Pulmonary smooth muscle differentiates from the lung mesenchyme in mouse and anole. Surprisingly, however, bioinformatic and experimental evidence suggest that pulmonary smooth muscle is derived from vascular smooth muscle in chicken. Furthermore, our data revealed differences in the timing and extent of smooth muscle innervation across species. These findings highlight how terrestrial vertebrates have evolutionarily repurposed similar morphogenetic motifs to build lungs that suit their energetic needs.