Nucleolar stress in Drosophila neuroblasts, a model for human ribosomopathies
Nucleolar stress in Drosophila neuroblasts, a model for human ribosomopathies
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DOI：
10.1242/bio.046565
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发表时间：
2020-04-01
期刊：
影响因子：
2.4
通讯作者：
DiMario, Patrick J.
中科院分区：
文献类型：
--
作者：
Baral, Sonu Shrestha;Lieux, Molly E.;DiMario, Patrick J.
不同的干细胞或祖细胞对功能性核糖体表现出不同的阈值要求。这对于几种人类核糖体疾病尤其正确，其中选择胚胎神经嵴细胞或成人骨髓干细胞，而不是其他核糖体，由于核糖体生物发生或功能失败（现在称为核仁应激）而表现出致命性。为了确定不同的果蝇神经母细胞是否对核仁应激表现出不同的敏感性，我们使用CRISPR-Cas9破坏编码两种剪接变异核糖体生物发生因子（rbf）的Nopp140基因。破坏Nopp140诱导核仁胁迫，使幼虫在二龄期停滞。当大多数成神经细胞幼虫停止发育时，蘑菇体（MB）成神经细胞继续增殖，这表明它们保持了deadpan，一种神经细胞特异性转录因子，并继续结合EdU。与其他神经母细胞相比，野生型幼虫的MB神经母细胞核仁中含有更多的纤维蛋白和Nopp140，这表明MB神经母细胞在胚胎发生晚期增殖时储存了RBFs，而其他神经母细胞通常进入静止状态。在1-2天大的幼虫的Nopp140-/- MB神经母细胞中，母体转录物编码的Nopp140更丰富，可能使这些细胞对核仁应激更有弹性。本文以第一人称采访了该论文的第一作者。
Different stem cells or progenitor cells display variable threshold requirements for functional ribosomes. This is particularly true for several human ribosomopathies in which select embryonic neural crest cells or adult bone marrow stem cells, but not others, show lethality due to failures in ribosome biogenesis or function (now known as nucleolar stress). To determine if various Drosophila neuroblasts display differential sensitivities to nucleolar stress, we used CRISPR-Cas9 to disrupt the Nopp140 gene that encodes two splice variant ribosome biogenesis factors (RBFs). Disruption of Nopp140 induced nucleolar stress that arrested larvae in the second instar stage. While the majority of larval neuroblasts arrested development, the mushroom body (MB) neuroblasts continued to proliferate as shown by their maintenance of deadpan, a neuroblast-specific transcription factor, and by their continued EdU incorporation. MB neuroblasts in wild-type larvae appeared to contain more fibrillarin and Nopp140 in their nucleoli as compared to other neuroblasts, indicating that MB neuroblasts stockpile RBFs as they proliferate in late embryogenesis while other neuroblasts normally enter quiescence. A greater abundance of Nopp140 encoded by maternal transcripts in Nopp140-/- MB neuroblasts of 1-2-day-old larvae likely rendered these cells more resilient to nucleolar stress.This article has an associated First Person interview with the first author of the paper.