Insufficient alveolar gas exchange capacity is a major contributor to lung disease. During lung development, a population of distal epithelial progenitors first produce bronchiolar-fated and subsequently alveolar-fated progeny. The mechanisms controlling this bronchiolar-to-alveolar developmental transition remain largely unknown. We developed a novel grafting assay to test if lung epithelial progenitors are intrinsically programmed or if alveolar cell identity is determined by environmental factors. These experiments revealed that embryonic lung epithelial identity is extrinsically determined. We show that both glucocorticoid and STAT3 signalling can control the timing of alveolar initiation, but that neither pathway is absolutely required for alveolar fate specification; rather, glucocorticoid receptor and STAT3 work in parallel to promote alveolar differentiation. Thus, developmental acquisition of lung alveolar fate is a robust process controlled by at least two independent extrinsic signalling inputs. Further elucidation of these pathways might provide therapeutic opportunities for restoring alveolar capacity.Medical Research Council (G0900424, ER), the March of Dimes (5-FY11-119, ER), the
Wellcome Trust (093029, ER), Newton Trust (14.07h, ER), Wellcome Trust PhD programme for
Clinicians (MN), Postdoctoral Fellowship from the Government of the Basque Country (UL),
MRC studentship (RVR), British Heart Foundation Studentship (EJB), COST BM1201. Core
grants from the Wellcome Trust (092096) and Cancer Research UK (C6946/A14492).This is the final version of the article. It first appeared from the Company of Biologists at http://dx.doi.org/10.1242/dev.134023
