Tissue specific roles for the ribosome biogenesis factor Wdr43 in zebrafish development.
Tissue specific roles for the ribosome biogenesis factor Wdr43 in zebrafish development.
复制标题
DOI：
10.1371/journal.pgen.1004074
复制
发表时间：
2014-01
期刊：
影响因子：
4.5
通讯作者：
Yelick PC
中科院分区：
文献类型：
--
作者：
Zhao C;Andreeva V;Gibert Y;LaBonty M;Lattanzi V;Prabhudesai S;Zhou Y;Zon L;McCann KL;Baserga S;Yelick PC
在脊椎动物颅面发育过程中，神经嵴细胞（NCCs）参与了颅面咽部骨骼的形成。导致颅面复合体畸形的NCC特化、迁移和分化缺陷与人类颅面疾病相关，包括由TCOF 1突变引起的Treacher-Collins综合征。据推测，干扰核糖体生物合成和p53介导的神经上皮细胞凋亡导致小鼠Tcof 1突变体中NCC发育不全。然而，连接核糖体生物合成和NCC发展的潜在机制仍然知之甚少。在这里，我们报告了一个新的斑马鱼突变体，fantome（风扇），其中含有一个点突变和预测过早终止密码子在斑马鱼wdr 43，直系同源酵母UTP 5。尽管wdr 43 mRNA在早期斑马鱼发育过程中广泛表达，并且其缺乏引发早期神经、眼、心脏和咽弓缺陷，但后来的缺陷似乎相当局限于NCC衍生的颅面软骨。在这里，我们表明，Wdr 43的C-末端，这是不存在的风扇突变蛋白，是必要的和足够的介导其核仁定位和蛋白质的相互作用在后生动物。我们证明，Wdr 43功能的核糖体生物合成，并在风扇突变体中观察到的缺陷介导的p53依赖性途径。最后，我们表明，适当的本地化的各种核仁蛋白，包括TCOF 1，是依赖于WDR 43。总之，我们的研究结果为Wdr 43在发育，核糖体生物发生以及核糖体病诱导的颅面表型（包括Treacher-Collins综合征）中的作用提供了新的见解。在这里，我们描述了一种新的斑马鱼颅面突变体，fantome（风扇），在wdr 43基因的点突变引起的识别和表征。虽然以前在酵母中被鉴定为UTP 5，一种在核糖体生物合成中起作用的核仁蛋白，但在这里，我们发现Wdr 43也调节早期斑马鱼发育，包括NCC的特异性和分化。核仁蛋白的突变已被发现是多种人类颅面综合征的病因，包括Treacher-Collins综合征（TCS），通常由TCOF 1的突变引起，TCOF 1在核糖体生物合成中也起着重要作用。然而，连接核糖体生物发生和NCC规格和分化成咽弓软骨的潜在机制仍然知之甚少。在这里，我们描述了风扇/wdr 43突变体表型，并提出功能特点的wdr 43在颅面发育。我们表明，WDR 43是所需的适当的核仁定位的各种核仁蛋白，包括TCOF 1/糖浆。这些研究提供了新的见解核糖体蛋白质功能的早期斑马鱼的发展，重点是NCC衍生的颅面发育，作为一个模型，为人类颅面神经critiories。
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. Here, we describe the identification and characterization of a novel zebrafish craniofacial mutant, fantome (fan), caused by a point mutation in the wdr43 gene. Although previously characterized as UTP5 in yeast, a nucleolar protein functioning in ribosome biogenesis, here we show that Wdr43 also 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 also plays important roles in ribosome biogenesis. However, the underlying mechanisms linking ribosomal biogenesis and NCC specification and differentiation into pharyngeal arch cartilages remains poorly understood. Here we describe the fan/wdr43 mutant phenotype, and present functional characterizations of Wdr43 in craniofacial development. We show that WDR43 is required for the proper nucleolar localization of a variety of nucleolar proteins, including TCOF1/Treacle. These studies provide new insight into ribosomal protein function in early zebrafish development, with focus on NCC derived craniofacial development, as a model for human craniofacial neurocristopathies.
登录
查看更多内容
影响因子：
14.9
作者：
Freed EF;Baserga SJ
通讯作者：
Baserga SJ
影响因子：
4.6
作者：
Bugner, Verena;Tecza, Aleksandra;Kuehl, Michael
通讯作者：
Kuehl, Michael
DOI：
10.1073/pnas.0603730103
发表时间：
2006-09-05
影响因子：
11.1
作者：
Dixon, Jill;Jones, Natalie C.;Trainor, Paul A.
通讯作者：
Trainor, Paul A.
影响因子：
1.5
作者：
Andreeva, Viktoria;Connolly, Michelle H.;Stewart-Swift, Caitlin;Fraher, Daniel;Burt, Jeffrey;Cardarelli, Justin;Yelick, Pamela C.
通讯作者：
Yelick, Pamela C.
影响因子：
64.8
作者：
Dragon, F;Gallagher, JEG;Baserga, SJ
通讯作者：
Baserga, SJ