Establishment of smooth muscle and cartilage juxtaposition in the developing mouse upper airways

Abstract

In the trachea and bronchi of the mouse, airway smooth muscle (SM) and cartilage are localized to complementary domains surrounding the airway epithelium. Proper juxtaposition of these tissues ensures a balance of elasticity and rigidity that is critical for effective air passage. It is unknown how this tissue complementation is established during development. Here we dissect the developmental relationship between these tissues by genetically disrupting SM formation (through Srf inactivation) or cartilage formation (through Sox9 inactivation) and assessing the impact on the remaining lineage. We found that, in the trachea and main bronchi, loss of SM or cartilage resulted in an increase in cell number of the remaining lineage, namely the cartilage or SM, respectively. However, only in the main bronchi, but not in the trachea, did the loss of SM or cartilage lead to a circumferential expansion of the remaining cartilage or SM domain, respectively. In addition to SM defects, cartilage-deficient tracheas displayed epithelial phenotypes, including decreased basal cell number, precocious club cell differentiation, and increased secretoglobin expression. These findings together delineate the mechanisms through which a cell-autonomous disruption of one structural tissue can have widespread consequences on upper airway function. Significance A balance of airway rigidity and elasticity is critical for uninterrupted airflow to and from the lungs. In the trachea and bronchi, this balance is achieved by the precise juxtaposition of smooth muscle (SM) and cartilage that together encircle the airway. We investigate how this juxtaposition is established during embryogenesis by using mouse mutants that lack either SM or cartilage in the developing lung. We demonstrate the nature of the antagonism between the nascent SM and cartilage lineages. Our results also reveal a role for cartilage in the proper differentiation of tracheal epithelium. Together these findings elucidate unique mechanisms of how airway SM or cartilage malformation may impact airway function.