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The Roles of RNA Polymerase I and III Subunits Polr1c and Polr1d in Craniofacial Development and in Zebrafish Models of Treacher Collins Syndrome.
PLoS Genet 2016; 12(7):e1006187PG

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+Show Affiliations

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.Stowers Institute for Medical Research, Kansas City, Missouri, United States of America.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.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.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.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27448281

Citation

Noack Watt, Kristin E., et al. "The Roles of RNA Polymerase I and III Subunits Polr1c and Polr1d in Craniofacial Development and in Zebrafish Models of Treacher Collins Syndrome." PLoS Genetics, vol. 12, no. 7, 2016, pp. e1006187.
Noack Watt KE, Achilleos A, Neben CL, et al. The Roles of RNA Polymerase I and III Subunits Polr1c and Polr1d in Craniofacial Development and in Zebrafish Models of Treacher Collins Syndrome. PLoS Genet. 2016;12(7):e1006187.
Noack Watt, K. E., Achilleos, A., Neben, C. L., Merrill, A. E., & Trainor, P. A. (2016). The Roles of RNA Polymerase I and III Subunits Polr1c and Polr1d in Craniofacial Development and in Zebrafish Models of Treacher Collins Syndrome. PLoS Genetics, 12(7), pp. e1006187. doi:10.1371/journal.pgen.1006187.
Noack Watt KE, et al. The Roles of RNA Polymerase I and III Subunits Polr1c and Polr1d in Craniofacial Development and in Zebrafish Models of Treacher Collins Syndrome. PLoS Genet. 2016;12(7):e1006187. PubMed PMID: 27448281.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Roles of RNA Polymerase I and III Subunits Polr1c and Polr1d in Craniofacial Development and in Zebrafish Models of Treacher Collins Syndrome. AU - Noack Watt,Kristin E, AU - Achilleos,Annita, AU - Neben,Cynthia L, AU - Merrill,Amy E, AU - Trainor,Paul A, Y1 - 2016/07/22/ PY - 2015/12/22/received PY - 2016/06/22/accepted PY - 2016/7/23/entrez PY - 2016/7/23/pubmed PY - 2017/3/23/medline SP - e1006187 EP - e1006187 JF - PLoS genetics JO - PLoS Genet. VL - 12 IS - 7 N2 - 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. SN - 1553-7404 UR - https://www.unboundmedicine.com/medline/citation/27448281/The_Roles_of_RNA_Polymerase_I_and_III_Subunits_Polr1c_and_Polr1d_in_Craniofacial_Development_and_in_Zebrafish_Models_of_Treacher_Collins_Syndrome_ L2 - http://dx.plos.org/10.1371/journal.pgen.1006187 DB - PRIME DP - Unbound Medicine ER -