title: Pathogenesis of POLR1C-dependent Type 3 Treacher Collins Syndrome revealed by a zebrafish model.
abstract: Treacher Collins Syndrome (TCS) is a rare congenital birth disorder (1 in 50,000 live births) characterized by severe craniofacial defects, including the downward slanting palpebral fissures, hypoplasia of the facial bones, and cleft palate (CP). Over 90% of patients with TCS have a mutation in the TCOF1 gene. However, some patients exhibit mutations in two new causative genes, POLR1C and POLR1D, which encode subunits of RNA polymerases I and III, that affect ribosome biogenesis. In this study, we examine the role of POLR1C in TCS using zebrafish as a model system. Our data confirmed that polr1c is highly expressed in the facial region, and dysfunction of this gene by knockdown or knock-out resulted in mis-expression of neural crest cells during early development that leads to TCS phenotype. Next generation sequencing and bioinformatics analysis of the polr1c mutants further demonstrated the up-regulated p53 pathway and predicted skeletal disorders. Lastly, we partially rescued the TCS facial phenotype in the background of p53 mutants, which supported the hypothesis that POLR1C-dependent type 3 TCS is associated with the p53 pathway.
authors.affiliation: Department of Biology, Hong Kong Baptist University, Hong Kong.
authors.forename: Marco Chi Chung
authors.initials: MC
authors.lastname: Lau
authors.affiliation: Department of Biology, Hong Kong Baptist University, Hong Kong.
authors.forename: Ernest Man Lok
authors.initials: EM
authors.lastname: Kwong
authors.affiliation: School of Biological Sciences, The University of Hong Kong, Hong Kong.
authors.forename: Keng Po
authors.initials: KP
authors.lastname: Lai
authors.affiliation: School of Life Sciences, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Jing-Woei
authors.initials: JW
authors.lastname: Li
authors.affiliation: Department of Biology, Hong Kong Baptist University, Hong Kong.
authors.forename: Jeff Cheuk Hin
authors.initials: JC
authors.lastname: Ho
authors.affiliation: School of Life Sciences, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Ting-Fung
authors.initials: TF
authors.lastname: Chan
authors.affiliation: Department of Biology, Hong Kong Baptist University, Hong Kong.
authors.forename: Chris Kong Chu
authors.initials: CK
authors.lastname: Wong
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Taiwan.
authors.forename: Yun-Jin
authors.initials: YJ
authors.lastname: Jiang
authors.affiliation: Department of Biology, Hong Kong Baptist University, Hong Kong. Electronic address: kftse@hkbu.edu.hk.
authors.forename: William Ka Fai
authors.initials: WK
authors.lastname: Tse
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D055786:Gene Knockout Techniques; D006801:Humans; D008342:Mandibulofacial Dysostosis / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; D009432:Neural Crest / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D015027:Zebrafish / Q000196:embryology / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins
keywords: Cleft palate; Craniofacial development; Disease model; Transcritpomic