Svep1 orchestrates distal airway patterning and alveolar differentiation in murine lung development

Disruptions in airway branching or alveolar differentiation during lung development can lead to severe respiratory deficiencies and neonatal death. The molecular mechanisms governing branching patterning and early alveolar formation remain elusive. Loss ofSvep1function in mice results in various developmental defects, including lung hypoplasia and perinatal lethality. Our examination of the lungs ofSvep1knockout (Svep1^-/-)mouse embryos, bothin vivoandin vitro, revealed thatSvep1mutants exhibit an increase in the number of disorganized distal airway tips and progressively greater disruption of lung lobe morphology over time and saccular development.Svep1interacts with FGF signaling to regulate smooth muscle differentiation and, together withFgf9,guides airway branching patterning. Transcriptomic data from the lungs ofSvep1^-/-embryos revealed dysregulated gene expression affecting saccular maturation. Our findings demonstrate thatSvep1is a key extracellular matrix player shaping airway morphology and influencing alveolar fate. These insights offer potential avenues for therapeutic interventions in congenital lung disorders.