Interplay of ECM organization, ROCK signaling, and cell polarity drives mesothelium formation and lung growth.

The mechanisms regulating organ size remain poorly understood. Here, we show that FREM2 is a critical modulator of lung size. Frem2 mutant mice exhibit defects in the formation of elastic fibers around mesothelial cells, which compromises phosphorylated myosin light chain (pMLC) signaling and mesothelial cell polarization, leading to lung growth inhibition. These processes are regulated in part through inhibition of p38-mediated upregulation of matrix metalloproteinase-2, as pharmacological decrease of p38 phosphorylation or MMP activity partially attenuates the Frem2 mutant lung phenotypes. Disruption of ROCK function also leads to defects in elastic fiber organization and mesothelial cell polarity, while inhibition of Vangl2-regulated mesothelial cell polarity causes defects in pMLC abundance and elastic fiber structure. Collectively, these processes constitute a positive feedback loop to regulate lung size. Notably, Frem2 mutant mice also display defects in the formation of the mesothelium and reduced growth of other internal organs. Importantly, patients with FREM2 mutations exhibit smaller lungs. These results reveal a shared role and mechanism for the mesothelium in organ size control.