The ribosome biogenesis factor Nol11 is required for optimal rDNA transcription and craniofacial development in Xenopus.
The ribosome biogenesis factor Nol11 is required for optimal rDNA transcription and craniofacial development in Xenopus.
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核糖体生物发生因子NOL11是最佳的rDNA转录和颅面发育所必需的。
DOI：
10.1371/journal.pgen.1005018
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发表时间：
2015-03
期刊：
影响因子：
4.5
通讯作者：
Khokha MK
中科院分区：
文献类型：
--
作者：
Griffin JN;Sondalle SB;Del Viso F;Baserga SJ;Khokha MK
核糖体的产生是普遍存在的，也是生命的基础。因此，令人惊讶的是，核糖体生物发生的缺陷是越来越多的遗传学上不同的遗传性疾病（统称为核糖体病）的基础。我们先前确定，核仁蛋白，NOL 11，是必不可少的最佳前rRNA转录和加工在人类组织培养细胞。然而，NOL 11在多细胞生物体发育中的作用仍然未知。在这里，我们揭示了NOL 11在脊椎动物核糖体生物合成和颅面发育中的关键功能。Nol 11在两栖动物和哺乳动物的颅神经嵴（CNC）发育中强烈表达，并且非洲爪蟾Nol 11的敲低导致前rRNA转录和加工受损、细胞凋亡增加和颅面软骨的异常发育。抑制p53挽救了这种骨骼表型，但不是潜在的核糖体生物合成缺陷，证明了一种进化上保守的控制机制，通过这种机制，核糖体受损的颅面细胞被去除。这种机制的过度激活会损害颅面发育。总之，我们的研究结果揭示了颅面发育对Nol 11的新需求，提出了第一个核糖体病的青蛙模型，并进一步深入了解了特定核糖体生物合成蛋白与颅面细胞存活之间的临床重要关系。所有细胞都需要核糖体，即生产蛋白质的细胞工厂。许多因素联合收割机产生了核糖体的多个复杂单元，其中许多仍然没有得到很好的理解。令人惊讶的是，尽管对核糖体的需求无处不在，但各种核糖体生物合成因子中的缺陷导致不同的组织特异性表型，统称为核糖体病。我们研究了一种核糖体生物合成因子Nol 11在胚胎发育过程中的作用，以确定它是否也具有组织特异性表型。在这里，我们表明，表达的nol 11是密切相关的发展中的头部在脊椎动物和不足的nol 11的结果在惊人的畸形颅面骨骼。我们进一步表明，减少Nol 11损害了核糖体生产的关键早期步骤，这引发了有助于头部的细胞群内的凋亡。增加的细胞死亡至少是Nol 11颅面缺陷的部分原因;减少细胞死亡可以挽救一些颅面表型，但不能挽救核糖体生物合成缺陷。总之，我们首次证明了Nol 11是脊椎动物头部正常发育所必需的，并为核糖体病的有趣组织倾向提供了新的见解。
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. 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.
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影响因子：
2.7
作者：
Griffin, John N.;Compagnucci, Claudia;Hu, Diane;Fish, Jennifer;Klein, Ophir;Marcucio, Ralph;Depew, Michael J.
通讯作者：
Depew, Michael J.
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：
Aybar, MJ;Nieto, MA;Mayor, R
通讯作者：
Mayor, R
影响因子：
64.8
作者：
Ebert, Benjamin L.;Pretz, Jennifer;Bosco, Jocelyn;Chang, Cindy Y.;Tamayo, Pablo;Galili, Naomi;Raza, Azra;Root, David E.;Attar, Eyal;Ellis, Steven R.;Golub, Todd R.
通讯作者：
Golub, Todd R.
影响因子：
--
作者：
Freed EF;Bleichert F;Dutca LM;Baserga SJ
通讯作者：
Baserga SJ