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bioRxiv · 10.1101/678581

Cyp26b1 is required for proper airway epithelial differentiation during lung development

Daniel, E.·Sutton, G.·Htike, Y.·Cleaver, O.
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Abstract

Proper organ development depends on coordinated communication between multiple cell types. Retinoic acid (RA) is an autocrine and paracrine signaling molecule critical for the development of most organs including the lung. Both RA excess and deficiency lead to drastic alterations in embryogenesis, often culminating in embryonic or neonatal lethality. Therefore, RA levels must be spatially and temporally titrated to ensure proper organogenesis. Despite extensive work detailing the effects of RA deficiency in early lung morphogenesis, little is known about how RA levels are modulated during late lung development. Here, we investigate the role of the RA catabolizing protein Cyp26b1 in lung development. Cyp26b1 is highly enriched in lung endothelial cells (ECs) throughout the course of development. We find that loss of Cyp26b1 impacts differentiation of the distal epithelium without appreciably affecting proximal airways, EC lineages, or stromal populations. Cyp26b1-/- lungs exhibit an increase in cellular density, with an expansion of distal progenitors at the expense of alveolar type 1 (AT1) cells, which culminates in neonatal death. Exogenous administration of RA in late gestation was able to partially reproduce this defect in epithelial differentiation; however, transcriptional analyses of Cyp26b1-/- lungs and RA-treated lungs reveal separate, but overlapping, transcriptional responses. These data suggest that the defects observed in Cyp26b1-/- lungs are caused by both RA-dependent and RA-independent mechanisms. This work highlights critical cellular crosstalk during lung development involving a crucial role for Cyp26b1-expressing endothelium, and identifies a novel RA rheostat in lung development.\n\nHIGHLIGHTSO_LICyp26b1 is highly expressed in lung ECs throughout development\nC_LIO_LICyp26b1-null lungs fail to undergo proper differentiation of distal epithelium leading to an increase in progenitors and AT2 cells at the expense of AT1 cells\nC_LIO_LIFunctional and transcriptional analyses suggest both RA-dependent and RA-independent mechanisms\nC_LI

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Daniel, E., Sutton, G., Htike, Y., Cleaver, O.. 2019-06-20. Cyp26b1 is required for proper airway epithelial differentiation during lung development. https://doi.org/10.1101/678581

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