Temporal regulation of metamorphic processes in Drosophila by the let-7 and miR-125 heterochronic microRNAs
Temporal regulation of metamorphic processes in Drosophila by the let-7 and miR-125 heterochronic microRNAs
复制标题
DOI：
10.1016/j.cub.2008.06.020
复制
发表时间：
2008-07-08
期刊：
影响因子：
9.2
通讯作者：
Johnston, Laura A.
中科院分区：
文献类型：
--
作者：
Caygill, Elizabeth E.;Johnston, Laura A.
背景：let-7和lin-4 microRNAs属于一类暂时表达的非编码调控rna，在线虫中起着异慢性开关基因的作用。异时基因控制发育过程中事件的相对时间，被认为是新形态快速进化的主要力量。let-7是高度保守的，在果蝇中暂时与lin-4同源物miR-125共调控。然而，对于它们在线虫之外的需求，或者它们是否普遍控制发育过程的时间，人们知之甚少。结果：我们报道了果蝇突变体的产生，该突变体缺乏let-7和miR-125活性，导致在变态过程中出现多效表型。我们将重点放在两个缺陷上，并证明let-7和miR-125的缺失会导致两个不同的变态过程的时间延迟：翅膀细胞周期终末退出和成人腹肌神经肌肉连接（NMJs）的成熟。我们发现编码核蛋白的突变（ab）基因是真正的let-7靶点，并提供证据表明let-7通过调节ab的表达来控制变态过程中腹部NMJs的成熟率。结论：果蝇let-7和miR-125突变体在特定的变态过程中表现出暂时的失调。与秀丽隐杆线虫一样，果蝇let-7对于特定细胞周期退出的适当时机既是必要的，也是充分的，这表明它作为异慢性microRNA的功能是保守的。ab基因是let-7的靶标，其在肌肉中的抑制对于变态过程中NMJ成熟的时机至关重要。我们的研究结果表明，let-7和miR-125作为从少年到成年生命阶段过渡所需事件的保守调节因子。
Background: The let-7 and lin-4 microRNAs belong to a class of temporally expressed, noncoding regulatory RNAs that function as heterochronic switch genes in the nematode C. elegans. Heterochronic genes control the relative timing of events during development and are considered a major force in the rapid evolution of new morphologies. let-7 is highly conserved and in Drosophila is temporally coregulated with the lin-4 homolog, miR-125. Little is known, however, about their requirement outside the nematode or whether they universally control the timing of developmental processes.Results: We report the generation of a Drosophila mutant that lacks let-7and miR-125 activities and that leads to a pleiotropic phenotype arising during metamorphosis. We focus on two defects and demonstrate that loss of let-7 and miR-125 results in temporal delays in two distinct metamorphic processes: the terminal cell-cycle exit in the wing and maturation of neuromuscular junctions (NMJs) at adult abdominal muscles. We identify the abrupt (ab) gene, encoding a nuclear protein, as a bona fide let-7 target and provide evidence that let-7 governs the maturation rate of abdominal NMJs during metamorphosis by regulating ab expression.Conclusions: Drosophila let-7 and miR-125 mutants exhibit temporal misregulation of specific metamorphic processes. As in C. elegans, Drosophila let-7 is both necessary and sufficient for the appropriate timing of a specific cell-cycle exit, indicating that its function as a heterochronic microRNA is conserved. The ab gene is a target of let-7, and its repression in muscle is essential for the timing of NMJ maturation during metamorphosis. Our results suggest that let-7 and miR-125 serve as conserved regulators of events necessary for the transition from juvenile to adult life stages.