Lats inactivation reveals hippo function in alveolar type I cell differentiation during lung transition to air breathing

Abstract

Lung growth to its optimal size at birth is driven by reiterative airway branching followed by differentiation and expansion of alveolar cell types. How this elaborate growth is coordinated with the constraint of the chest is poorly understood. Here we investigate the role of Hippo signaling, a cardinal pathway in organ size control. Unexpectedly, we found that epithelial loss of the Hippo kinase genes Lats1 and Lats2 (Lats1/2) leads to a striking reduction of lung size due to an early arrest of branching morphogenesis. This growth defect is accompanied by abnormalities in epithelial cell polarity, cell division plane, extracellular matrix deposition and precocious and increased expression of markers for type 1 alveolar epithelial cell (AEC1), a terminal differentiation marker. Increased AEC1s was also observed in transgenics with overexpression of a constitutive nuclear form of downstream transcriptional effector YAP. Conversely, loss of Yap and Taz led to decreased AEC1s, demonstrating that the canonical Hippo signaling pathway is both sufficient and necessary to drive AEC1 fate. These findings together revealed unique roles of Hippo-LATS-YAP signaling in the developing lung.