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, in mouse lung development. Unexpectedly, we found that epithelial loss of the Hippo kinase genes Lats1 and Lats2 (Lats1/2) leads to a striking reduction of lung size owing to an early arrest of branching morphogenesis. This growth defect is accompanied by abnormalities in epithelial cell polarity, cell division plane and extracellular matrix deposition, as well as precocious and increased expression of markers for type 1 alveolar epithelial cells (AEC1s), an indicator of terminal differentiation. Increased AEC1s were also observed in transgenic mice 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 reveal unique roles of Hippo-LATS-YAP signaling in the developing mouse lung.

Yap and its subcellular localization have distinct compartment-specific roles in the developing lung

“…Although preserving its pseudostratified organization, multiple clumps of cells strongly labeled by nuclear Yap appeared in the lumen, detached from the airway epithelium. This phenotype was reminiscent of that reported in Lats1/2-null, Crb3-null and other mouse lines that result in Yap constitutive nuclear expression (Lange et al, 2015;Lin et al, 2015;Mahoney, 2014;Nantie et al, 2018;Otsubo et al, 2017;Szymaniak et al, 2015;Zhao et al, 2014). Interestingly, this hyperplastic phenotype was not associated with a significant increase in cell proliferation (Fig.…”

“…Shh Cre -mediated deletion of Mst1/2 or Lats1/2, leading to the expected nuclear Yap accumulation from the loss of Hippo kinase function, also resulted in disruption of lung development. However, the lung phenotypes differ markedly between these mutants (Lange et al, 2015;Lin et al, 2015;Nantie et al, 2018). Lats1/2-null lungs were severely hypoplastic and had major defects in branching morphogenesis, reminiscent of that seen in Yap-deficient lungs.…”

“…More fundamentally, information was missing about the role of Yap and its nucleocytoplasmic shuttling in compartmentspecific events in the absence of potential confounding effects of Hippo kinase inactivation. Lastly, evidence of the preferential localization of Yap in the nucleus or cytoplasm of the developing lung has been inconclusive because of conflicting results from different reports (Lange et al, 2015;Lin et al, 2015Lin et al, , 2017Mahoney et al, 2014;Nantie et al, 2018;Szymaniak et al, 2015). Although informative, these studies revealed major gaps of knowledge and left key questions open.…”

Hippo‐Yap/Taz signaling: Complex network interactions and impact in epithelial cell behavior

“…Yap accumulates in the nucleus of these cells, in stark contrast to the cytoplasmic Yap localization in the cuboidal alveolar type 2 (AT2) cells (Z. Liu et al, 2016;Nantie et al, 2018;van Soldt et al, 2019). Mechanical tension plays a significant role in perinatal differentiation of these cell types (J.…”

Homeostatic and tumourigenic activity of SOX2+ pituitary stem cells is controlled by the LATS/YAP/TAZ cascade

“…The Hippo pathway controls stem cell proliferation and tumourigenesis in several organs such as in the liver 16, 17 , intestines 18 and lung 19, 20 . In the core phosphorylation cascade, MST1/2 kinases phosphorylate and activate LATS1/2 serine/threonine-protein kinases, which in turn phosphorylate co-activators Yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1, a.k.a.…”