Tissue specific roles for the ribosome biogenesis factor Wdr43 in zebrafish development.
During vertebrate craniofacial development, neural crest cells (NCCs) contribute to most of the craniofacial pharyngeal skeleton. Defects in NCC specification, migration and differentiation resulting in malformations in the craniofacial complex are associated with human craniofacial disorders including Treacher-Collins Syndrome, caused by mutations in TCOF1. It has been hypothesized that perturbed ribosome biogenesis and resulting p53 mediated neuroepithelial apoptosis results in NCC hypoplasia in mouse Tcof1 mutants. However, the underlying mechanisms linking ribosome biogenesis and NCC development remain poorly understood. Here we report a new zebrafish mutant, fantome (fan), which harbors a point mutation and predicted premature stop codon in zebrafish wdr43, the ortholog to yeast UTP5. Although wdr43 mRNA is widely expressed during early zebrafish development, and its deficiency triggers early neural, eye, heart and pharyngeal arch defects, later defects appear fairly restricted to NCC derived craniofacial cartilages. Here we show that the C-terminus of Wdr43, which is absent in fan mutant protein, is both necessary and sufficient to mediate its nucleolar localization and protein interactions in metazoans. We demonstrate that Wdr43 functions in ribosome biogenesis, and that defects observed in fan mutants are mediated by a p53 dependent pathway. Finally, we show that proper localization of a variety of nucleolar proteins, including TCOF1, is dependent on that of WDR43. Together, our findings provide new insight into roles for Wdr43 in development, ribosome biogenesis, and also ribosomopathy-induced craniofacial phenotypes including Treacher-Collins Syndrome.
Department of Oral and Maxillofacial Pathology, Division of Craniofacial and Molecular Genetics, Tufts University, Boston, Massachusetts, United States of America ; Institute of Evolution and Marine Biodiversity, Ocean University of China, Qingdao, China.
Chengtian
C
Zhao
Department of Oral and Maxillofacial Pathology, Division of Craniofacial and Molecular Genetics, Tufts University, Boston, Massachusetts, United States of America.
Viktoria
V
Andreeva
Department of Oral and Maxillofacial Pathology, Division of Craniofacial and Molecular Genetics, Tufts University, Boston, Massachusetts, United States of America.
Yann
Y
Gibert
Department of Oral and Maxillofacial Pathology, Division of Craniofacial and Molecular Genetics, Tufts University, Boston, Massachusetts, United States of America.
Melissa
M
LaBonty
Department of Oral and Maxillofacial Pathology, Division of Craniofacial and Molecular Genetics, Tufts University, Boston, Massachusetts, United States of America.
Victoria
V
Lattanzi
Department of Oral and Maxillofacial Pathology, Division of Craniofacial and Molecular Genetics, Tufts University, Boston, Massachusetts, United States of America.
Shubhangi
S
Prabhudesai
Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts, United States of America.
Yi
Y
Zhou
Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts, United States of America.
Leonard
L
Zon
Department of Genetics, Yale School of Medicine, New Haven, Connecticut, United States of America.
Kathleen L
KL
McCann
Department of Genetics, Yale School of Medicine, New Haven, Connecticut, United States of America ; Departments of Molecular Biophysics & Biochemistry and Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut, United States of America.
Susan
S
Baserga
Department of Oral and Maxillofacial Pathology, Division of Craniofacial and Molecular Genetics, Tufts University, Boston, Massachusetts, United States of America.
Pamela C
PC
Yelick
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002356:Cartilage / Q000254:growth & development / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008342:Mandibulofacial Dysostosis / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009432:Neural Crest / Q000166:cytology / Q000254:growth & development*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D060066:Protein Interaction Maps / Q000235:genetics; D012270:Ribosomes / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics* / Q000254:growth & development; D029961:Zebrafish Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
D036341:Intercellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D016159:Tumor Suppressor Protein p53; C000588911:Wdr43 protein, zebrafish; D029961:Zebrafish Proteins; C572551:nolc1 protein, zebrafish; C571228:tp53 protein, zebrafish