The Ribosome Biogenesis Protein Nol9 Is Essential for Definitive Hematopoiesis and Pancreas Morphogenesis in Zebrafish.
The Ribosome Biogenesis Protein Nol9 Is Essential for Definitive Hematopoiesis and Pancreas Morphogenesis in Zebrafish.
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DOI：
10.1371/journal.pgen.1005677
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发表时间：
2015-12
期刊：
影响因子：
4.5
通讯作者：
Cvejic A
中科院分区：
文献类型：
--
作者：
Bielczyk-Maczyńska E;Lam Hung L;Ferreira L;Fleischmann T;Weis F;Fernández-Pevida A;Harvey SA;Wali N;Warren AJ;Barroso I;Stemple DL;Cvejic A
核糖体生物合成是细胞中普遍存在的重要过程。核糖体生物发生和功能的缺陷导致一组人类疾病，统称为核糖体病。在这项研究中，我们描述了一个斑马鱼突变体与nol 9，一个基因，编码一个非核糖体蛋白参与rRNA加工的功能丧失突变。nol 9 sa 1022/sa 1022突变体在28 S rRNA加工中存在缺陷。nol 9 sa 1022/sa 1022幼虫表现出胰腺、肝脏和肠道发育不全，并且造血干细胞和祖细胞（HSPC）以及定形红细胞和淋巴细胞数量减少。此外，超微结构分析揭示了发生在尾静脉内皮细胞中的病理过程的迹象，强调了在nol 9 sa 1022/sa 1022幼虫中观察到的表型的复杂性。我们进一步表明nol 9 sa 1022/sa 1022胚胎中胰腺和造血缺陷是由于各自祖细胞的细胞增殖受损。有趣的是，TP 53的遗传缺失拯救了HSPC，但没有拯救胰腺缺陷。相比之下，通过L-亮氨酸处理经由mTOR途径激活mRNA翻译不会逆转红细胞或胰腺缺陷。总之，我们提出了nol 9 sa 1022/sa 1022突变体，一种新的斑马鱼核糖体病模型，它概括了人类疾病的关键特征。使用这种遗传上易于处理的模型将增强我们对完整脊椎动物中核糖体生物合成受损后的组织特异性机制的理解。核糖体是蛋白质合成的机器，它的产生是所有细胞的基础。这是一个非常复杂的过程，需要核糖体和非核糖体蛋白的协调作用。核糖体形成和功能的损害导致一类称为“核糖体病”的疾病。在这里，我们描述了斑马鱼nol 9突变体的鉴定和表征，nol 9是一种编码参与核糖体生物合成的非核糖体蛋白的基因。nol 9 sa 1022/sa 1022突变体由于受损的细胞增殖而在胰腺外分泌和红细胞中显示出缺陷。nol 9 sa 1022/sa 1022突变体的这些表型特征使人联想到Shwachman-Diamond综合征的临床症状，该综合征是一种以胰腺外分泌功能不全和造血缺陷为特征的核糖体病。有趣的是，我们发现nol 9 sa 1022/sa 1022幼虫的造血而不是胰腺形态发生是TP 53依赖的，这突出表明同一生物体内不同组织之间受损的核糖体生物发生的后果不同。这项研究为核糖体生物合成蛋白Nol 9在斑马鱼发育中的功能提供了新的见解，并提出了一种新的模型，将有助于破译核糖体病的组织特异性机制。
Ribosome biogenesis is a ubiquitous and essential process in cells. Defects in ribosome biogenesis and function result in a group of human disorders, collectively known as ribosomopathies. In this study, we describe a zebrafish mutant with a loss-of-function mutation in nol9, a gene that encodes a non-ribosomal protein involved in rRNA processing. nol9 sa1022/sa1022 mutants have a defect in 28S rRNA processing. The nol9 sa1022/sa1022 larvae display hypoplastic pancreas, liver and intestine and have decreased numbers of hematopoietic stem and progenitor cells (HSPCs), as well as definitive erythrocytes and lymphocytes. In addition, ultrastructural analysis revealed signs of pathological processes occurring in endothelial cells of the caudal vein, emphasizing the complexity of the phenotype observed in nol9 sa1022/sa1022 larvae. We further show that both the pancreatic and hematopoietic deficiencies in nol9 sa1022/sa1022 embryos were due to impaired cell proliferation of respective progenitor cells. Interestingly, genetic loss of Tp53 rescued the HSPCs but not the pancreatic defects. In contrast, activation of mRNA translation via the mTOR pathway by L-Leucine treatment did not revert the erythroid or pancreatic defects. Together, we present the nol9 sa1022/sa1022 mutant, a novel zebrafish ribosomopathy model, which recapitulates key human disease characteristics. The use of this genetically tractable model will enhance our understanding of the tissue-specific mechanisms following impaired ribosome biogenesis in the context of an intact vertebrate. The production of ribosomes, the protein-synthesizing machines, is fundamental in all cells. It is a very complex process that requires the coordinated actions of ribosomal and non-ribosomal proteins. Impairment of ribosome formation and function leads to a class of disorders known as “ribosomopathies”. Here, we describe the identification and characterization of a zebrafish mutant in nol9, a gene encoding a non-ribosomal protein involved in ribosome biogenesis. The nol9 sa1022/sa1022 mutants show defects in the exocrine pancreas and erythrocytes due to impaired cell proliferation. These phenotypic features of nol9 sa1022/sa1022 mutants are reminiscent of the clinical symptoms of Shwachman-Diamond syndrome, a ribosomopathy characterized by exocrine pancreatic insufficiency and hematopoietic defects. Interestingly, we found that hematopoiesis but not pancreas morphogenesis in nol9 sa1022/sa1022 larvae is Tp53-dependent, highlighting that the consequences of impaired ribosome biogenesis differ between tissues within the same organism. This study provides novel insight into the function of the ribosome biogenesis protein Nol9 in zebrafish development and presents a novel model that will help to decipher the tissue-specific mechanisms of ribosomopathies.