Abstract
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.
Highlights
Neural crest cells (NCCs), a transient cell type that is unique to vertebrates, originate from the dorsal aspect of the neural tube during embryogenesis
Previously characterized as UTP5 in yeast, a nucleolar protein functioning in ribosome biogenesis, here we show that Wdr43 regulates early zebrafish development, including NCC specification and differentiation
Mutations in nucleolar proteins have been found to be causative for a variety of human craniofacial syndromes including Treacher-Collins Syndrome (TCS), often caused by mutations in TCOF1, which plays important roles in ribosome biogenesis
Summary
Neural crest cells (NCCs), a transient cell type that is unique to vertebrates, originate from the dorsal aspect of the neural tube during embryogenesis. After undergoing an epithelial-to-mesenchymal transition (EMT), NCCs migrate along well defined pathways, and eventually inhabit peripheral destinations where they differentiate into diverse derivatives, including melanocytes, craniofacial cartilage and bone, smooth muscle, and neuronal lineages. Defects in CNCC development are associated with craniofacial malformations, one of the most common of human birth defects [3]. Treacher-Collins syndrome (TCS), an autosomal dominant congenital disorder of craniofacial development, characterized by mandibulofacial dysostosis including cleft palate and hypoplasia of the facial bones, is most commonly associated with mutations in the TCOF1 gene [4]. Extensive research in the mouse model has shown that mutations in Tcof disrupt ribosome biogenesis, resulting in impaired proliferation and subsequent apoptosis of neuroepithelial and NCC precursors, which in turn results in reduced numbers of NCCs migrating into the developing craniofacial complex [10]. Inhibition of p53 function can rescue craniofacial abnormalities in mouse Tcof mutants, without rescuing ribosome biogenesis defects [11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
