Abstract
Branching morphogenesis is a fundamental program for tissue patterning. We show that active YAP, a key mediator of Hippo signaling, is distributed throughout the murine lung epithelium and loss of epithelial YAP severely disrupts branching. Failure to branch is restricted to regions where YAP activity is removed. This suggests that YAP controls local epithelial cell properties. In support of this model, mechanical force production is compromised and cell proliferation is reduced in Yap mutant lungs. We propose that defective force generation and insufficient epithelial cell number underlie the branching defects. Through genomic analysis, we also uncovered a feedback control of pMLC levels, which is critical for mechanical force production, likely through the direct induction of multiple regulators by YAP. Our work provides a molecular pathway that could control epithelial cell properties required for proper morphogenetic movement and pattern formation.
Highlights
Development of the lung has served as a model system to study fundamental questions such as branching morphogenesis, epithelial-mesenchymal interactions and cell-type specification
To assess the sites of active Yes-associated protein (YAP) at different stages of lung development, we examined the subcellular distribution of YAP protein in the lung epithelium by immunofluorescence and immunohistochemistry
We did not observe a sharp transition of YAP from the cytoplasm to the nucleus at the junction between the SOX2+ and SOX9+ populations, a region dubbed the transition zone (TZ) (Figure 1W), as previously reported (Mahoney et al, 2014)
Summary
Development of the lung has served as a model system to study fundamental questions such as branching morphogenesis, epithelial-mesenchymal interactions and cell-type specification. The buds grow ventrally and caudally, and initiate lateral branches at invariant positions, beginning around 10.5 days post coitus (dpc) in mice In this way, five buds are generated, four on the right side and one on the left side, leading to the formation of four right lobes (cranial, middle, accessory and caudal) and one left lobe of the mature mouse lung. Five buds are generated, four on the right side and one on the left side, leading to the formation of four right lobes (cranial, middle, accessory and caudal) and one left lobe of the mature mouse lung In this process, proximal-distal specification is associated with the emergence of Sox9-expressing progenitors and non-branching Sox2-expressing airways, which will become the conducting airway in the mature lung (Yang and Chen, 2014). Acquisition of the spatial and temporal sequence of lung morphogenesis forms the basis of understanding the molecular mechanisms of lung development
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