Transmural pressure signals through retinoic acid to regulate lung branching.

TitleTransmural pressure signals through retinoic acid to regulate lung branching.
Publication TypeJournal Article
Year of Publication2022
AuthorsJaslove, JM, Goodwin, K, Sundarakrishnan, A, Spurlin, JW, Mao, S, Košmrlj, A, Nelson, CM
Date Published2022 Jan 15
KeywordsAnimals, Cells, Cultured, Computer Simulation, Epithelial Cells, Lung, Mice, Morphogenesis, Myocytes, Smooth Muscle, Receptors, Retinoic Acid, Signal Transduction, Stress, Mechanical, Tretinoin

<p>During development, the mammalian lung undergoes several rounds of branching, the rate of which is tuned by the relative pressure of the fluid within the lumen of the lung. We carried out bioinformatics analysis of RNA-sequencing of embryonic mouse lungs cultured under physiologic or sub-physiologic transmural pressure and identified transcription factor-binding motifs near genes whose expression changes in response to pressure. Surprisingly, we found retinoic acid (RA) receptor binding sites significantly overrepresented in the promoters and enhancers of pressure-responsive genes. Consistently, increasing transmural pressure activates RA signaling, and pharmacologically inhibiting RA signaling decreases airway epithelial branching and smooth muscle wrapping. We found that pressure activates RA signaling through the mechanosensor Yap. A computational model predicts that mechanical signaling through Yap and RA affects lung branching by altering the balance between epithelial proliferation and smooth muscle wrapping, which we test experimentally. Our results reveal that transmural pressure signals through RA to balance the relative rates of epithelial growth and smooth muscle differentiation in the developing mouse lung and identify RA as a previously unreported component in the mechanotransduction machinery of embryonic tissues.</p>

Alternate JournalDevelopment
PubMed ID35051272
PubMed Central IDPMC8917413
Grant ListR21 HL110335 / HL / NHLBI NIH HHS / United States
F30 HL139039 / HL / NHLBI NIH HHS / United States
F32 HL137273 / HL / NHLBI NIH HHS / United States
R21 HL118532 / HL / NHLBI NIH HHS / United States
R01 HL120142 / HL / NHLBI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
R01 HL164861 / HL / NHLBI NIH HHS / United States
R01 HD099030 / HD / NICHD NIH HHS / United States