期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1862, 期 6, 页码 1147-1158出版社
ELSEVIER
DOI: 10.1016/j.bbadis.2016.03.005
关键词
Disease model; Cleft palate; Craniofacial development; Transcritpomic
资金
- Faculty Research Grant, Hong Kong Baptist University [FRG1/12-13/044, FRG1/13-14/010, FRG1/13-14/064]
- Lee Shau Kee Donation [LSK/1415/P06]
- Lo Kwee-Seong Biomedical Research Fund
- Lee Hysan Foundation
- National Health Research Institutes, Taiwan [MG-103-PP-13, MG-104-PP-12]
- Ministry of Science and Technology, Taiwan [MOST 103-2311-B-400-001, MOST104-2311-B-400-001]
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. (C) 2016 Elsevier B.V. All rights reserved.
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