Smooth muscle differentiation shapes domain branches during mouse lung development.

TitleSmooth muscle differentiation shapes domain branches during mouse lung development.
Publication TypeJournal Article
Year of Publication2019
AuthorsGoodwin, K, Mao, S, Guyomar, T, Miller, E, Radisky, DC, Košmrlj, A, Nelson, CM
JournalDevelopment
Volume146
Issue22
Date Published2019 11 25
ISSN1477-9129
KeywordsActins, Animals, Cell Differentiation, Cell Proliferation, Crosses, Genetic, Epithelial Cells, Epithelium, Female, Gene Expression Regulation, Developmental, Genotype, Lung, Male, Mesoderm, Mice, Morphogenesis, Muscle, Smooth, Organogenesis, Protein Domains, Signal Transduction
Abstract

<p>During branching morphogenesis, a simple cluster of cells proliferates and branches to generate an arborized network that facilitates fluid flow. The overall architecture of the mouse lung is established by domain branching, wherein new branches form laterally off the side of an existing branch. The airway epithelium develops concomitantly with a layer of smooth muscle that is derived from the embryonic mesenchyme. Here, we examined the role of smooth muscle differentiation in shaping emerging domain branches. We found that the position and morphology of domain branches are highly stereotyped, as is the pattern of smooth muscle that differentiates around the base of each branch. Perturbing the pattern of smooth muscle differentiation genetically or pharmacologically causes abnormal domain branching. Loss of smooth muscle results in ectopic branching and decreases branch stereotypy. Increased smooth muscle suppresses branch initiation and extension. Computational modeling revealed that epithelial proliferation is insufficient to generate domain branches and that smooth muscle wrapping is required to shape the epithelium into a branch. Our work sheds light on the physical mechanisms of branching morphogenesis in the mouse lung.</p>

DOI10.1242/dev.181172
Alternate JournalDevelopment
PubMed ID31645357
PubMed Central IDPMC6899029
Grant ListR01 HD099030 / HD / NICHD NIH HHS / United States
R01 HL120142 / HL / NHLBI NIH HHS / United States
R21 HL110335 / HL / NHLBI NIH HHS / United States
R21 HL118532 / HL / NHLBI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States