PUBLICATION
Small molecule screen identifies elafibranor to link mechanical cues and IRF6-dependent epithelial differentiation
- Authors
- Molteni, H.L., Golden, B., Yu, E.P.Y., Liao, E.C.
- ID
- ZDB-PUB-260113-15
- Date
- 2026
- Source
- Disease models & mechanisms : (Journal)
- Registered Authors
- Liao, Eric
- Keywords
- Enveloping layer, Epiboly, Epithelial differentiation, Periderm, Small molecule screen
- MeSH Terms
-
- Animals
- Cell Adhesion/drug effects
- Cell Differentiation*/drug effects
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/metabolism
- Epithelial Cells*/cytology
- Epithelial Cells*/drug effects
- Epithelial Cells*/metabolism
- Epithelium/drug effects
- Epithelium/embryology
- Epithelium/metabolism
- Gastrulation/drug effects
- Gene Expression Regulation, Developmental/drug effects
- Interferon Regulatory Factors*/metabolism
- Small Molecule Libraries*/pharmacology
- Zebrafish*/embryology
- Zebrafish*/genetics
- Zebrafish*/metabolism
- Zebrafish Proteins*/metabolism
- PubMed
- 41527516 Full text @ Dis. Model. Mech.
Citation
Molteni, H.L., Golden, B., Yu, E.P.Y., Liao, E.C. (2026) Small molecule screen identifies elafibranor to link mechanical cues and IRF6-dependent epithelial differentiation. Disease models & mechanisms. :.
Abstract
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/PPARd 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 wildtype 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping