Abstract
Laminin-binding integrins regulate critical morphogenic processes, but their specific roles in lung development are unknown. In this study, we combined an in vivo model of epithelial α3 subunit deletion in the murine lung with a multiomics approach to investigate the role of the epithelial α3β1 integrin during murine lung development. We demonstrate that α3β1 integrin is dispensable for airway branching morphogenesis due to delayed epithelial expression. Instead, in vivo deletion of α3β1 integrin impaired alveolar epithelial cell differentiation and disrupted alveolar-capillary barrier formation, functionally limiting gas exchange. A discontinuous alveolar BM contained abnormal collagen IV and laminin networks and widened the gap between epithelial and endothelial cells in the alveolar-capillary barrier niche. Mechanistically, mice deficient in epithelial α3β1 integrin possessed an intracellular trafficking and secretion defect for BM components. Thus, integrin α3β1 orchestrates the temporal maturation of alveolar epithelial cells required for organization of the alveolar-capillary barrier.