RESUMO
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.
Assuntos
Antioxidantes , Benzotiazóis , Modelos Animais de Doenças , Disostose Mandibulofacial , Estresse Oxidativo , Espécies Reativas de Oxigênio , Tolueno/análogos & derivados , Proteína Supressora de Tumor p53 , Proteínas de Peixe-Zebra , Peixe-Zebra , Animais , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Disostose Mandibulofacial/genética , Disostose Mandibulofacial/tratamento farmacológico , Antioxidantes/farmacologia , Benzotiazóis/farmacologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Tolueno/farmacologia , Crista Neural/efeitos dos fármacos , Crista Neural/metabolismo , Apoptose/efeitos dos fármacos , RNA Polimerase I/antagonistas & inibidores , RNA Polimerase I/metabolismo , RNA Polimerase I/genéticaRESUMO
Mandibulofacial dysostosis (Treacher Collins syndrome) is associated with clinical abnormalities of structures derived from the first and second branchial arches, including antimongoloid slant of palpebral fissures, colobomas of the lower eyelid, eyelash malformations, and malar and mandibular defects. We describe an unusual clinical feature associated with colobomas of the lower eyelids, in a patient with mandibulofacial dysostosis, successfully treated with botulinum toxin and subsequent surgery.