title: Cnbp ameliorates Treacher Collins Syndrome craniofacial anomalies through a pathway that involves redox-responsive genes.
abstract: Treacher Collins Syndrome (TCS) is a rare congenital disease (1:50 000 live births) characterized by craniofacial defects, including hypoplasia of facial bones, cleft palate and palpebral fissures. Over 90% of the cases are due to mutations in the TCOF1 gene, which codifies the nucleolar protein Treacle. Here we report a novel TCS-like zebrafish model displaying features that fully recapitulate the spectrum of craniofacial abnormalities observed in patients. As it was reported for a Tcof1+/-mouse model, Treacle depletion in zebrafish caused reduced rRNA transcription, stabilization of Tp53 and increased cell death in the cephalic region. An increase of ROS along with the overexpression of redox-responsive genes was detected; furthermore, treatment with antioxidants ameliorated the phenotypic defects of craniofacial anomalies in TCS-like larvae. On the other hand, Treacle depletion led to a lowering in the abundance of Cnbp, a protein required for proper craniofacial development. Tcof1 knockdown in transgenic zebrafish overexpressing cnbp resulted in barely affected craniofacial cartilage development, reinforcing the notion that Cnbp has a role in the pathogenesis of TCS. The cnbp overexpression rescued the TCS phenotype in a dose-dependent manner by a ROS-cytoprotective action that prevented the redox-responsive genes' upregulation but did not normalize the synthesis of rRNAs. Finally, a positive correlation between the expression of CNBP and TCOF1 in mesenchymal cells from both control and TCS subjects was found. Based on this, we suggest CNBP as an additional target for new alternative therapeutic treatments to reduce craniofacial defects not only in TCS but also in other neurocristopathies.
authors.affiliation: IBR (Instituto de Biología Molecular y Celular de Rosario), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario (UNR), Ocampo y Esmeralda, Rosario, 2000 Argentina.
authors.forename: Mauro S Porcel
authors.initials: MS
authors.lastname: de Peralta
authors.affiliation: IBR (Instituto de Biología Molecular y Celular de Rosario), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario (UNR), Ocampo y Esmeralda, Rosario, 2000 Argentina.
authors.forename: Valeria S
authors.initials: VS
authors.lastname: Mouguelar
authors.affiliation: IBR (Instituto de Biología Molecular y Celular de Rosario), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario (UNR), Ocampo y Esmeralda, Rosario, 2000 Argentina.
authors.forename: María Antonella
authors.initials: MA
authors.lastname: Sdrigotti
authors.affiliation: Departmento de Genetica e Biologia Evolutiva, Instituto de Biociencias, Universidade de São Paulo, Rua do Matao, 277, Sala 200. Sao Paulo, Brazil.
authors.forename: Felipe A A
authors.initials: FA
authors.lastname: Ishiy
authors.affiliation: Departmento de Genetica e Biologia Evolutiva, Instituto de Biociencias, Universidade de São Paulo, Rua do Matao, 277, Sala 200. Sao Paulo, Brazil.
authors.forename: Roberto D
authors.initials: RD
authors.lastname: Fanganiello
authors.affiliation: Departmento de Genetica e Biologia Evolutiva, Instituto de Biociencias, Universidade de São Paulo, Rua do Matao, 277, Sala 200. Sao Paulo, Brazil.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Passos-Bueno
authors.affiliation: IBR (Instituto de Biología Molecular y Celular de Rosario), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario (UNR), Ocampo y Esmeralda, Rosario, 2000 Argentina.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Coux
authors.affiliation: IBR (Instituto de Biología Molecular y Celular de Rosario), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario (UNR), Ocampo y Esmeralda, Rosario, 2000 Argentina.
authors.forename: Nora B
authors.initials: NB
authors.lastname: Calcaterra
mesh_terms: D000818:Animals; D019465:Craniofacial Abnormalities / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D004625:Embryo, Nonmammalian / Q000378:metabolism; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D008342:Mandibulofacial Dysostosis / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D008648:Mesoderm / Q000378:metabolism; D008954:Models, Biological; D010084:Oxidation-Reduction; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C433227:CNBP protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; C499019:cnbpa protein, zebrafish