The Hippo pathway effectors TAZ and YAP are sequentially required in lung development

Abstract

Background: Transcriptional co-activator with PDZ-binding motif (TAZ) and Yes-associated protein (YAP) are key downstream effectors of the Hippo pathway. TAZ is considered as a homolog of YAP. Recent studies revealed that TAZ knockout mice exhibit lung emphysema, while YAP knockout mice show abnormalities in bronchial morphogenesis, and the cause of these differences remains unknown. Objective: To compare the role of TAZ and YAP in lung development, by generating lung epithelial-specific conditional knockout mice (cKO mice) of Taz and Yap. Methods: Taz and Yap cKO mice were generated by using a surfactant protein C-driven Cre recombinase allele. To identify genes affected by Yap ablation from lung epithelial cells, RNA-seq analysis was performed in Yap cKO embryo lung. We confirmed our in vivo findings by using human lung epithelial cell lines, which YAP and TAZ were suppressed by siRNA. Results: In lung development, Yap was highly expressed in embryonic stage of lung development, conversely Taz was highly expressed in the early alveolar stage. Taz cKO adult mice exhibited lung emphysema in adults, whereas Yap cKO mice were lethal at birth and showed bronchial branching abnormalities. RNA-seq analysis revealed that YAP ablation decreased Sonic hedgehog (Shh) expression, which is essential in proper branching morphogenesis. We also found that TGF-beta stimulation induces Shh expression in cell lines, which was suppressed by knockdown of TAZ or YAP. Conclusion: Our results indicate that TAZ and YAP function at different stages of lung development in lung epithelial cells and essential for proper lung development. Our results suggested the existence of a novel pathway between TGF-beta and Shh.