Postnatal FGF-signalling establishes gradients of cell-identities along the proximal-distal axis of the lung airways

The spatial organization and developmental control of cell maturation in the branched airway epithelium are only partially understood. Here, we labelled the major adult secretory epithelial cell-types and analysed them at single-cell resolution. We found opposing and partially overlapping graded gene-expression programs along the proximal-distal axis of the airways, on top of a general program that relates to detoxification. The first program is proximally elevated and relates to innate immunity and the second is enriched distally and relates to lipid metabolism, ion transport and antigen presentation. Cells at intermediate locations express lower levels of both programs and show increased levels of differentiation potency in vitro, suggesting a graded distribution of functionalities along the airway network. Lineage-tracing combined with single-cell RNA sequencing of airway secretory cells at four developmental stages showed that these gradients are established sequentially in common postnatal progenitors. Fgfr2b expression is distally enriched and its inactivation in postnatal airways leads to a reduction in the levels of distal gene-expression programs and an expansion of proximal genes into distally located airway cells. This suggests a central role of FGF-signalling in tissue-scale airway patterning. ### Competing Interest Statement The authors have declared no competing interest.