PUBLICATION
egr3 is a mechanosensitive transcription factor gene required for cardiac valve morphogenesis
- Authors
- da Silva, A.R., Gunawan, F., Boezio, G.L.M., Faure, E., Théron, A., Avierinos, J.F., Lim, S., Jha, S.G., Ramadass, R., Guenther, S., Looso, M., Zaffran, S., Juan, T., Stainier, D.Y.R.
- ID
- ZDB-PUB-240516-5
- Date
- 2024
- Source
- Science advances 10: eadl0633eadl0633 (Journal)
- Registered Authors
- Juan, Thomas, Stainier, Didier
- Keywords
- none
- Datasets
- GEO:GSE241935, GEO:GSE242483
- MeSH Terms
-
- Animals
- Early Growth Response Protein 3*/genetics
- Early Growth Response Protein 3*/metabolism
- Endothelial Cells/metabolism
- Gene Expression Regulation, Developmental
- Heart Valves*/embryology
- Heart Valves*/metabolism
- Humans
- Mechanotransduction, Cellular
- Morphogenesis*/genetics
- Swine
- Zebrafish*
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- PubMed
- 38748804 Full text @ Sci Adv
Citation
da Silva, A.R., Gunawan, F., Boezio, G.L.M., Faure, E., Théron, A., Avierinos, J.F., Lim, S., Jha, S.G., Ramadass, R., Guenther, S., Looso, M., Zaffran, S., Juan, T., Stainier, D.Y.R. (2024) egr3 is a mechanosensitive transcription factor gene required for cardiac valve morphogenesis. Science advances. 10:eadl0633eadl0633.
Abstract
Biomechanical forces, and their molecular transducers, including key mechanosensitive transcription factor genes, such as KLF2, are required for cardiac valve morphogenesis. However, klf2 mutants fail to completely recapitulate the valveless phenotype observed under no-flow conditions. Here, we identify the transcription factor EGR3 as a conserved biomechanical force transducer critical for cardiac valve formation. We first show that egr3 null zebrafish display a complete and highly penetrant loss of valve leaflets, leading to severe blood regurgitation. Using tissue-specific loss- and gain-of-function tools, we find that during cardiac valve formation, Egr3 functions cell-autonomously in endothelial cells, and identify one of its effectors, the nuclear receptor Nr4a2b. We further find that mechanical forces up-regulate egr3/EGR3 expression in the developing zebrafish heart and in porcine valvular endothelial cells, as well as during human aortic valve remodeling. Altogether, these findings reveal that EGR3 is necessary to transduce the biomechanical cues required for zebrafish cardiac valve morphogenesis, and potentially for pathological aortic valve remodeling in humans.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping