Abstract
The conducting airway forms a protective mucosal barrier and is the primary target of airway disorders. The molecular events required for the formation and function of the airway mucosal barrier, as well as the mechanisms by which barrier dysfunction leads to early onset airway diseases, remain unclear. In this study, we systematically characterized the developmental landscape of the mouse airway using single-cell RNA sequencing and identified remarkably conserved cellular programs operating during human fetal development. We demonstrated that in mouse, genetic inactivation of chloride channel Ano1/Tmem16a compromises airway barrier function, results in early signs of inflammation, and alters the airway cellular landscape by depleting epithelial progenitors. Mouse Ano1-/-mutants exhibited mucus obstruction and abnormal mucociliary clearance that resemble the airway defects associated with cystic fibrosis. The data reveal critical and non-redundant roles for Ano1 in organogenesis, and show that chloride channels are essential for mammalian airway formation and function.
Highlights
The highly conserved respiratory system of air breathing animals represents a major interface between internal organs and the outer environment
Because Ano1 and CFTR are expressed in orthologous cell types of mouse and human airway epithelium, respectively, our work provides a tractable animal model for understanding the roles of chloride channels in human airway development and pathogenesis
Using fluorescently labeled Jacalin, a plant-based lectin that recognizes airway glycoproteins and mucin components (Ostedgaard et al, 2017), as well as antibody against SCGB1A1, a low-molecular-weight protein enriched in airway secretory cells, we observed a massive expansion of the secretory cell population in Ano1-/- knockout airway at postnatal day 0 (P0) (Figure 1A; Figure 1—figure supplement 1A)
Summary
The highly conserved respiratory system of air breathing animals represents a major interface between internal organs and the outer environment. In the course of a typical human lifespan, approximately 200 to 400 million liters of air are conducted via the respiratory system (Ganesan et al, 2013; Rackley and Stripp, 2012). While airway function has been adapted for organismal physiology and aging (Sharma and Goodwin, 2006), it remains vulnerable to deleterious genetic and environmental factors. Cystic fibrosis (CF), which primarily targets the respiratory system, is one of the most common recessively inherited disorder caused by the deficient CFTR gene that encodes a chloride channel (Stoltz et al, 2015). The main features of CF airway diseases include mucus obstruction and repetitive infections and inflammation, which often lead to severe
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