Foxn4 influences alveologenesis during lung development

The terminal stage of lung development begins with the formation of the terminal sacs followed by subdivision of these sacs by septa into numerous alveoli to maximize the gas-exchange surface. This process requires coordinated action of various intrinsic and extrinsic factors as well as interaction of epithelial and mesenchymal cells. We show here that during murine lung development, the Foxn4 transcription factor is expressed in proximal airways by a subpopulation of postmitotic epithelial cells which are distinct from basal and ciliated cells and of which only a small fraction are Clara cells. Targeted inactivation of Foxn4 causes dilated alveoli, thinned alveolar walls, and reduced septa in the distal lung but no overt gross alterations in proximal airways. The alveolar defects in mutants may result from decreased platelet-derived growth factor-A (PDGFA) signaling and reduced surfactant protein B (SFTPB) expression. These data together suggest that Foxn4 may have a non-cell-autonomous role critical for alveologenesis during lung development.