biostudies-literatureUnknownZhang KNHLBI NIH HHSLung size control and cell type specification are key unresolved issues. In this study, we have engineered mosaic patterns of Hippo signaling to reveal the developmental potential of SOX9⁺ progenitors at the distal lung buds. Our results show that the distal SOX9⁺ subdomain is sufficient to direct lung outgrowth through bifurcation, providing a mechanism for lung size control. Through single-cell analyses, we identify transitional cell states and candidates for promoting cell fates. Moreover, genetic analysis reveals that Hippo signaling induces distinct cell fates at different SOX9⁺ subdomains to produce the conducting airways and the alveolar epithelium. These results provide the first map of the developmental paths of lung cells. Some of the developmentabioRxiv : the preprint server for biology2025.10.28.684989https://www.ebi.ac.uk/biostudies/studies/S-EPMC12636293biostudies-literatureHippo signaling differentially regulates distal progenitor subpopulations and their transitional states to construct the mammalian lungs.PMC12636293R01 HL157446Zhang KChuang PTZaher YBasak MWang SAAung TYao EfalseHippo signaling differentially regulates distal progenitor subpopulations and their transitional states to construct the mammalian lungs.Lung size control and cell type specification are key unresolved issues. In this study, we have engineered mosaic patterns of Hippo signaling to reveal the developmental potential of SOX9⁺ progenitors at the distal lung buds. Our results show that the distal SOX9⁺ subdomain is sufficient to direct lung outgrowth through bifurcation, providing a mechanism for lung size control. Through single-cell analyses, we identify transitional cell states and candidates for promoting cell fates. Moreover, genetic analysis reveals that Hippo signaling induces distinct cell fates at different SOX9⁺ subdomains to produce the conducting airways and the alveolar epithelium. These results provide the first map of the developmental paths of lung cells. Some of the developmenta2025-01-01T00:00:00Z2025 Nov2026-07-02T03:15:58.194Z2026-07-02T03:08:54.291ZS-EPMC126362934127886710.1101/2025.10.28.684989