PUBLICATION
p53 inhibitor or antioxidants reduce the severity of ethmoid plate deformities in zebrafish Type 3 Treacher Collins syndrome model
- Authors
- Ulhaq, Z.S., You, M.S., Jiang, Y.J., Tse, W.K.F.
- ID
- ZDB-PUB-240401-2
- Date
- 2024
- Source
- International journal of biological macromolecules 266(Pt 2): 131216 (Journal)
- Registered Authors
- Jiang, Yun-Jin, Ulhaq, Zulvikar Syambani
- Keywords
- Antioxidative machinery, Apoptosis, Neural crest cells
- MeSH Terms
-
- Animals
- Antioxidants*/pharmacology
- Apoptosis/drug effects
- Benzothiazoles*/pharmacology
- Disease Models, Animal*
- Epithelial-Mesenchymal Transition/drug effects
- Mandibulofacial Dysostosis*/drug therapy
- Mandibulofacial Dysostosis*/genetics
- Neural Crest/drug effects
- Neural Crest/metabolism
- Oxidative Stress*/drug effects
- RNA Polymerase I/antagonists & inhibitors
- RNA Polymerase I/genetics
- RNA Polymerase I/metabolism
- Reactive Oxygen Species*/metabolism
- Toluene/analogs & derivatives*
- Toluene/pharmacology
- Tumor Suppressor Protein p53*/genetics
- Tumor Suppressor Protein p53*/metabolism
- Zebrafish*
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- PubMed
- 38556235 Full text @ Int. J. Biol. Macromol.
Citation
Ulhaq, Z.S., You, M.S., Jiang, Y.J., Tse, W.K.F. (2024) p53 inhibitor or antioxidants reduce the severity of ethmoid plate deformities in zebrafish Type 3 Treacher Collins syndrome model. International journal of biological macromolecules. 266(Pt 2):131216.
Abstract
Treacher Collins syndrome-3 (TCS-3) is a rare congenital craniofacial disorder attributed to variants in the RNA pol I subunit C (POLR1C). The pathogenesis of TCS-3 linked to polr1c involves the activation of apoptosis-dependent p53 pathways within neural crest cells (NCCs). This occurs due to disruptions in ribosome biogenesis, and the restoration of polr1c expression in early embryogenesis effectively rescues the observed craniofacial phenotype in polr1c-deficient zebrafish. Clinical variability in TCS patients suggests interactions between genes and factors like oxidative stress. Elevated production of reactive oxygen species (ROS) in epithelial cells may worsen phenotypic outcomes in TCS individuals. Our study confirmed excessive ROS production in facial regions, inducing apoptosis and altering p53 pathways. Deregulated cell-cycle and epithelial-to-mesenchymal transition (EMT) genes were also detected in the TCS-3 model. Utilizing p53 inhibitor (Pifithrin-α; PFT-α) or antioxidants (Glutathione; GSH and N-Acetyl-L-cysteine; NAC) effectively corrected migrated NCC distribution in the pharyngeal arch (PA), suppressed oxidative stress, prevented cell death, and modulated EMT inducers. Crucially, inhibiting p53 activation or applying antioxidants within a specific time window, notably within 30 h post-fertilization (hpf), successfully reversed phenotypic effects induced by polr1c MO.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping