Cnbp ameliorates Treacher Collins Syndrome craniofacial anomalies through a pathway that involves redox-responsive genes

PORCEL DE PERALTA, MAURO S.; MOUGUELAR, VALERIA S.; SDRIGOTTI, M. A.; ISHIY, F.A.A.; FAGANIELLO, R.D.; PASSOS-BUENO, M.R; COUX, GABRIELA (CO-CORRESPONDING); CALCATERRA, NORA B

Cell Death & Disease

Nature Pub. Group

Lugar: Londres; Año: 2016 vol. 7

Treacher-CollinsSyndrome (TCS) is a rare congenital disease (1:50000 live births) characterizedby craniofacial defects, including hypoplasia of facial bones, cleft palate andpalpebral fissures. Over 90% of the cases are due to mutations in the TCOF1 gene, which codifies the nucleolarprotein Treacle. Here we report a novel TCS-like zebrafish model displaying featuresthat fully recapitulate the spectrum of craniofacial abnormalities observed in patients.As it was reported for a Tcof1+/− mouse model, Treacle depletion inzebrafish caused reduced rRNA transcription, stabilization of Tp53 and increasedcell death in the cephalic region. An increase of ROS along with theoverexpression of redox-responsive genes was detected; furthermore, treatmentwith antioxidants ameliorated the phenotypic defects of craniofacial anomaliesin TCS-like larvae. On the other hand, Treacle depletion led to a lowering inthe abundance of Cnbp, a protein required for proper craniofacial development. Tcof1-knockdown in transgenic zebrafishover-expressing cnbp resulted in barelyaffected craniofacial cartilage development, reinforcing the notion that Cnbpplays a role in the pathogenesis of TCS. The cnbp overexpression rescued the TCS phenotype in a dose-dependentmanner by a ROS-cytoprotective action that prevented the redox-responsive genesup-regulation but did not normalize the synthesis of rRNAs. Finally, a positivecorrelation between the expression of CNBPand TCOF1 in mesenchymal cells from bothcontrol and TCS subjects was found. Based on this, we suggest CNBP as an additionaltarget for new alternative therapeutic treatments to reduce craniofacialdefects not only in TCS but also in other neurocristopathies.