AUTHOR=Cheong Sek-Shir , Akram Khondoker M. , Matellan Carlos , Kim Sally Yunsun , Gaboriau David C. A. , Hind Matthew , del Río Hernández Armando E. , Griffiths Mark , Dean Charlotte H. 

TITLE=The Planar Polarity Component VANGL2 Is a Key Regulator of Mechanosignaling

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=8

YEAR=2020

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2020.577201

DOI=10.3389/fcell.2020.577201

ISSN=2296-634X

ABSTRACT=<p>VANGL2 is a component of the planar cell polarity (PCP) pathway, which regulates tissue polarity and patterning. The <italic>Vangl2</italic><sup><italic>Lp</italic></sup> mutation causes lung branching defects due to dysfunctional actomyosin-driven morphogenesis. Since the actomyosin network regulates cell mechanics, we speculated that mechanosignaling could be impaired when VANGL2 is disrupted. Here, we used live-imaging of precision-cut lung slices (PCLS) from <italic>Vangl2</italic><sup><italic>Lp/+</italic></sup> mice to determine that alveologenesis is attenuated as a result of impaired epithelial cell migration. <italic>Vangl2</italic><sup><italic>Lp/+</italic></sup> tracheal epithelial cells (TECs) and alveolar epithelial cells (AECs) exhibited highly disrupted actomyosin networks and focal adhesions (FAs). Functional assessment of cellular forces confirmed impaired traction force generation in <italic>Vangl2</italic><sup><italic>Lp/+</italic></sup> TECs. YAP signaling in <italic>Vangl2</italic><sup><italic>Lp</italic></sup> airway epithelium was reduced, consistent with a role for VANGL2 in mechanotransduction. Furthermore, activation of RhoA signaling restored actomyosin organization in <italic>Vangl2</italic><sup><italic>Lp/+</italic></sup>, confirming RhoA as an effector of VANGL2. This study identifies a pivotal role for VANGL2 in mechanosignaling, which underlies the key role of the PCP pathway in tissue morphogenesis.</p>