A small-molecule screen identifies that elafibranor links mechanical cues and Irf6-dependent epithelial differentiation

The periderm is a transient epithelial layer with crucial roles in maintaining barrier integrity and preventing abnormal adhesions during midface development. Interferon regulatory factor 6 (IRF6) is a key genetic driver of periderm function. Zebrafish irf6 maternal-null embryos fail to form the periderm precursor epithelial population, termed the enveloping layer (EVL), resulting in embryonic rupture prior to gastrulation. We utilized this irf6 maternal-null model to perform a chemical screen and found that elafibranor, a dual PPARα/PPARδ agonist, delayed rupture and rescued irf6 maternal-null embryos to initiate gastrulation. Elafibranor treatment restored EVL cell-cell contacts, F-actin morphology and Zo1 localization at multiway junctions. Elafibranor also partially rescued expression of epithelial differentiation markers esrp1, tp63 and cebpb. Surprisingly, EVL structural changes preceded epithelial differentiation gene expression, suggesting that intercellular mechanical forces influence Irf6-mediated epithelial differentiation. Further, elafibranor-exposed wild-type zebrafish displayed characteristics of exacerbated adhesion, including axis shortening, craniofacial cartilage dysmorphology and elongated periderm microridges, as possible sequelae of apical epithelial constriction. These findings provide new insights into the complex interplay between tissue-level mechanical cues and transcriptional changes during early epithelial and embryonic development.