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Title: The Ribosome Biogenesis Factor Nol11 Is Required for Optimal rDNA Transcription and Craniofacial Development in Xenopus}
Article:
Abstract:
The production of ribosomes is ubiquitous and fundamental to life. As such, it is surprising that defects in ribosome biogenesis underlie a growing number of symptomatically distinct inherited disorders, collectively called ribosomopathies. We previously determined that the nucleolar protein, NOL11, is essential for optimal pre-rRNA transcription and processing in human tissue culture cells. However, the role of NOL11 in the development of a multicellular organism remains unknown. Here, we reveal a critical function for NOL11 in vertebrate ribosome biogenesis and craniofacial development. Nol11 is strongly expressed in the developing cranial neural crest( CNC) of both amphibians and mammals, and knockdown of Xenopus nol11 results in impaired pre-rRNA transcription and processing, increased apoptosis, and abnormal development of the craniofacial cartilages. Inhibition of p53 rescues this skeletal phenotype, but not the underlying ribosome biogenesis defect, demonstrating an evolutionarily conserved control mechanism through which ribosome-impaired craniofacial cells are removed. Excessive activation of this mechanism impairs craniofacial development. Together, our findings reveal a novel requirement for Nol11 in craniofacial development, present the first frog model of a ribosomopathy, and provide further insight into the clinically important relationship between specific ribosome biogenesis proteins and craniofacial cell survival.
Introduction:
The synthesis of ribosomes, the protein-manufacturing entities in cells, is fundamental to all of life. Therefore, it is surprising that defects in ribosome synthesis are compatible with the development of a multicellular organism, albeit with substantial morbidity. Several diseases of ribosome biogenesis, so-called ribosomopathies, have been described with a strikingly heterogeneous collection of symptomatologies[1–16]. The remarkable diversity of affected tissues across the ribosomopathies raises the question of how different cell types can be selectively affected by defects in the ubiquitous process of making ribosomes. An emerging class of ribosomopathies includes craniofacial anomalies. Craniofacial malformations are associated with over 700 human congenital syndromes, and the molecular causes of many of these diseases remain unknown[17]. Often the structures affected in craniofacial syndromes are derivatives of the cranial neural crest( CNC), a vertebrate specific, multipotent cell population that gives rise to a vast array of craniofacial tissues, including the majority of the craniofacial skeleton[6, 17–24]. Correct development of the CNC is a multistep process that includes specification at the border of the embryonic neural and non-neural ectoderm, delamination, migration to the facial primordia, proliferation and differentiation into normal craniofacial structure and morphology. This elaborate process requires extensive cellular modifications, and is carefully regulated at the molecular level[25–34]. Due to the clinical importance of the CNC, and their potential for regenerative medicine based treatment strategies, a detailed understanding of the control mechanisms underlying CNC development is a primary goal of craniofacial research. Investigations into the surprising relationship between craniofacial disease and defects in ribosome biogenesis are beginning to emerge. Defects in CNC derived craniofacial structures are associated with the ribosomopathy known as Treacher-Collins Syndrome[6, 15, 16, 21]. In Treacher-Collins syndrome patients, mutations in the TCOF, POLR1C or POLR1D genes result in impaired rDNA transcription and activation of the p53 mediated stress response in CNC cells[5, 6, 16]. Heterozygote mouse models of Treacher-Collins syndrome in certain genetic backgrounds recapitulate these craniofacial defects, which are dependent on p53 activation[6, 21]. These results suggest that mechanisms regulating CNC survival may be particularly sensitive to defects in ribosome production. Ribosome biogenesis begins with the assembly of the nucleolus around ribosomal DNA( rDNA) repeats and with the transcription of the polycistronic pre-ribosomal RNA( rRNA) precursor that contains the sequences for the 18S, 5. 8S and 28S rRNAs by RNA polymerase I( RNAPI). Over 200 ribosome biogenesis factors then process these rRNAs through a complex series of cleavages and modifications to assemble into the mature small( 40S) and large( 60S) subunits of the ribosome by incorporating 80 ribosomal proteins and the 5S rRNA[35–38]. Maturation of the 18S rRNA is mediated by a large ribonucleoprotein called the small subunit( SSU) processome[39–41]. Previous work in yeast has revealed that members of the t-Utp/UtpA sub-complex of the SSU( Utp4, Utp5, Utp8, Utp9, Utp10, Utp15 and Utp17) are required for both optimal transcription and processing of the pre-rRNA[42]. Likewise, the orthologs of most of these proteins are also required for pre-rRNA processing and transcription in human cells. The one exception is human Utp4, which is required for pre-rRNA processing but not for RNAPI transcription[40]. Mutation of Wdr43, the zebrafish ortholog of yeast Utp5, results in p53 mediated craniofacial malformations[42, 43]. Interestingly, while the majority of t-UTP/UTPA sub-complex proteins are conserved from yeast to humans, Utp8 and Utp9 constitute notable exceptions, suggesting that these t-Utp proteins may have evolved specific functions in vertebrates[40]. We recently discovered the human analog of yeast Utp8 to be NOL11, a metazoan-specific nucleolar protein[44, 45]. NOL11 was discovered by its interaction with the C-terminal region of the known t-UTP/UTPA subcomplex member, hUTP4/Cirhin, the protein mutated in North American Indian childhood cirrhosis( NAIC)[4, 44]. NOL11 is localized to the nucleolus, the site of ribosome biogenesis, where it associates with other proteins in the SSU processome to facilitate maturation of the small ribosomal subunit( 40S). The NAIC mutation in hUTP4/Cirhin reduces interaction with NOL11, implicating NOL11 in the pathogenesis of NAIC. NOL11 is required to maintain nucleolar number and for pre-rRNA transcription and processing in human tissue culture cells but its requirement in embryogenesis remains unknown[44]. Here, we used the frog Xenopus tropicalis to investigate its role in vertebrate development. We report that nol11 mRNA expression is strongly associated with the developing CNC in both amphibians and mice. We further demonstrate that nol11 is required for optimal pre-rRNA transcription and pre-rRNA processing in Xenopus, and that nol11 knockdown results in activation of the nucleolar stress response, p53 stabilization, and a dramatic craniofacial phenotype. Importantly, the craniofacial defect can be partially rescued by p53 depletion, while the underlying transcriptional defect cannot, demonstrating that the pathology is due to the cellular response to impaired ribosome biogenesis. Together, our findings reveal a novel requirement for Nol11 in craniofacial development and provide further insight into the evolutionarily conserved relationship between specific ribosome biogenesis factors and the control mechanisms that regulate CNC survival and development.
Discussion:
Ribosome biogenesis is a vital and energy intensive process, requiring the interaction of hundreds of proteins and the majority of a cell’s transcriptional output. As such, it is not surprising that it is carefully monitored, or that a control mechanism such as the nucleolar stress response exists to remove compromised cells. Indeed, impaired ribosome production is frequently associated with apoptosis. For example, Treacher-Collins syndrome is molecularly characterized by impaired ribosome biogenesis, activation of the nucleolar stress response and increased p53 levels in CNC cells[6, 21]. A similar increase in apoptosis has been reported to underlie the zebrafish Wdr43( Utp5) craniofacial phenotype[43]. Importantly, the observation that inhibition of apoptosis can rescue the cartilage phenotype but not the underlying transcriptional and processing defect in both Xenopus nol11 morphants and some mouse Treacher-Collins Syndrome models demonstrates that it is the evolutionary conserved nucleolar stress response, and not the ribosomal defect per se, that produces the craniofacial malformation. As such, further investigation and modulation of this stress response may ultimately provide novel treatment options for apoptosis induced ribosomopathies. Together with previous studies, our data provide further evidence that the CNC are particularly sensitive to insufficiency of certain ribosome biogenesis proteins and reveal a common, evolutionarily conserved control mechanism through which compromised multipotent CNC are eliminated in the embryo. This sensitivity of CNC to ribosome biogenesis defects also suggests that mutations in nucleolar factors may contribute to additional currently unexplained human congenital defects. The finding that defects in presumably globally required ribosome biogenesis factors can produce tissue specific defects is an intriguing emerging facet of embryonic development. Several human diseases are now known to result from mutations in ribosome production and present with distinct phenotypes[1–4, 6, 8, 9, 11, 14, 16, 44, 64, 65]. The mechanisms underlying the tissue specificity of these ribosome biogenesis factors remain unknown but may include differential ribosomal biogenesis factor requirements during the development of distinct tissues or a heightened sensitivity to impaired protein production in particular cell populations. While the CNC is a highly active embryonic cell population, the distinct phenotypes observed in human ribosomopathies, many of which do not include craniofacial defects, would seem to argue against the latter scenario. Furthermore, experimental support for the differential requirements hypothesis is beginning to emerge from studies of both mice and zebrafish[6, 43, 57, 66]. Our findings that nol11 expression at the mRNA level is tightly linked to CNC cells, where it is required for normal differentiation and development of craniofacial cartilages, but not detected in, or associated with overt defects in the development of several other active cell populations at similar stages, provides strong support for the possibility of differential ribosomal protein requirements during embryonic development. While beyond the scope of this work, a future comparison of RNA translation and protein profiles between the CNC and non-CNC cells of wild-type and knockdown embryos would be highly informative. Importantly, the role of the NOL11 protein in ribosome biogenesis is conserved between human cells and X. tropicalis embryos. In HeLa cells[44] and in developing frog embryos, depletion of NOL11 results in defects in pre-rRNA transcription and pre-18S rRNA processing. However, the precise pattern of the pre-rRNAs differs between the two species even in the non-depleted state, with the pattern in X. tropicalis similar to that found in zebrafish( D. rerio)[43, 67]. Whether this is due to differences among vertebrate species or differences between tissue culture cells and a developing organism we do not yet know. The development of oligonucleotide probes to study these pre-rRNA pathways in X. tropicalis should thus facilitate the mapping of steps in pre-rRNA processing in this developing frog. In summary, we have demonstrated a novel role for nol11 in vertebrate ribosome biogenesis, cell survival and craniofacial development. The emerging relationship between specific ribosome biogenesis factors and tissue specific developmental defects is an unexpected and intriguing feature of developmental biology, and one that may underlie numerous currently unexplained congenital syndromes. Our findings provide insight into this relationship and highlight the utility of Xenopus tropicalis as a model for further investigations of human ribosomopathies.
All cells require ribosomes , the cellular factories that produce proteins . A host of factors combine to produce the multiple complex units of a ribosome , many of which are still not well understood . Surprisingly , despite the ubiquitous requirement for ribosomes , defects in various ribosome biogenesis factors cause distinct and tissue specific phenotypes , collectively known as ribosomopathies . We examined the role of one ribosome biogenesis factor , Nol11 , during embryonic development to determine if it too had a tissue specific phenotype . Here we show that expression of nol11 is strongly associated with the developing head in vertebrates and that insufficient Nol11 results in striking malformations of the craniofacial skeleton . We further show that reduced Nol11 impairs critical early steps in ribosome production , which triggers apoptosis within cell populations that contribute to the head . Increased cell death is at least partially the cause of the Nol11 craniofacial defect; reducing cell death rescues some of the craniofacial phenotype but not the ribosome biogenesis defect . In summary , we demonstrate for the first time that Nol11 is required for normal development of the vertebrate head and provide novel insight into the intriguing tissue proclivity of ribosomopathies .