title: The Roles of RNA Polymerase I and III Subunits Polr1c and Polr1d in Craniofacial Development and in Zebrafish Models of Treacher Collins Syndrome.
abstract: Ribosome biogenesis is a global process required for growth and proliferation of all cells, yet perturbation of ribosome biogenesis during human development often leads to tissue-specific defects termed ribosomopathies. Transcription of the ribosomal RNAs (rRNAs) by RNA polymerases (Pol) I and III, is considered a rate limiting step of ribosome biogenesis and mutations in the genes coding for RNA Pol I and III subunits, POLR1C and POLR1D cause Treacher Collins syndrome, a rare congenital craniofacial disorder. Our understanding of the functions of individual RNA polymerase subunits, however, remains poor. We discovered that polr1c and polr1d are dynamically expressed during zebrafish embryonic development, particularly in craniofacial tissues. Consistent with this pattern of activity, polr1c and polr1d homozygous mutant zebrafish exhibit cartilage hypoplasia and cranioskeletal anomalies characteristic of humans with Treacher Collins syndrome. Mechanistically, we discovered that polr1c and polr1d loss-of-function results in deficient ribosome biogenesis, Tp53-dependent neuroepithelial cell death and a deficiency of migrating neural crest cells, which are the primary progenitors of the craniofacial skeleton. More importantly, we show that genetic inhibition of tp53 can suppress neuroepithelial cell death and ameliorate the skeletal anomalies in polr1c and polr1d mutants, providing a potential avenue to prevent the pathogenesis of Treacher Collins syndrome. Our work therefore has uncovered tissue-specific roles for polr1c and polr1d in rRNA transcription, ribosome biogenesis, and neural crest and craniofacial development during embryogenesis. Furthermore, we have established polr1c and polr1d mutant zebrafish as models of Treacher Collins syndrome together with a unifying mechanism underlying its pathogenesis and possible prevention.
authors.affiliation: Stowers Institute for Medical Research, Kansas City, Missouri, United States of America.|Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, United States of America.
authors.forename: Kristin E
authors.identifier: 0000-0003-3933-6946
authors.initials: KE
authors.lastname: Noack Watt
authors.affiliation: Stowers Institute for Medical Research, Kansas City, Missouri, United States of America.
authors.forename: Annita
authors.initials: A
authors.lastname: Achilleos
authors.affiliation: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, California, United States of America.|Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Neben
authors.affiliation: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, California, United States of America.|Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Merrill
authors.affiliation: Stowers Institute for Medical Research, Kansas City, Missouri, United States of America.|Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, United States of America.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Trainor
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000503:physiopathology; D012321:DNA-Directed RNA Polymerases / Q000096:biosynthesis / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D047108:Embryonic Development / Q000235:genetics; D006801:Humans; D008342:Mandibulofacial Dysostosis / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D009432:Neural Crest / Q000254:growth & development*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development
chemical_list: D016159:Tumor Suppressor Protein p53; D012321:DNA-Directed RNA Polymerases; C569283:POLR1C protein, human; C569282:POLR1D protein, human