Cyp26b1 is a critical regulator of distal airway epithelial differentiation during lung development

Abstract

Proper organ development depends on coordinated communication between multiple cell types. Retinoic acid (RA) is an autocrine and paracrine signaling molecule critical to development of most organs, including lung. Despite extensive work detailing effects of RA deficiency in early lung morphogenesis, little is known about how RA regulates late gestational lung maturation. Here, we investigate the role of the RA catabolizing protein Cyp26b1 in the lung. Cyp26b1 is highly enriched in lung endothelial cells (ECs) throughout development. We find that loss of Cyp26b1 leads to reduction of alveolar type 1 (AT1) cells, failure of alveolar inflation, and early postnatal lethality. Furthermore, we observe expansion of distal epithelial progenitors, but no appreciable changes in proximal airways, ECs, or stromal populations. Exogenous administration of RA during late gestation partially mimics these defects; however, transcriptional analyses comparing Cyp26b1−/− and RA-treated lungs reveal overlapping, but distinct, responses. These data suggest that defects observed in Cyp26b1−/− lungs are caused by both RA-dependent and RA-independent mechanisms. This work reports critical cellular crosstalk during lung development involving Cyp26b1-expressing endothelium and identifies a novel RA modulator in lung development.