Epithelial cell-turnover ensures robust coordination of tissue growth in Drosophila ribosomal protein mutants.
Epithelial cell-turnover ensures robust coordination of tissue growth in Drosophila ribosomal protein mutants.
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DOI：
10.1371/journal.pgen.1009300
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发表时间：
2021-01
期刊：
影响因子：
4.5
通讯作者：
Igaki T
中科院分区：
文献类型：
--
作者：
Akai N;Ohsawa S;Sando Y;Igaki T
通过细胞增殖和细胞死亡的稳健的、时间依赖性的协调来实现高度可再现的组织发育。为了研究稳健的组织生长的机制，我们分析了果蝇微小突变体（一系列核糖体蛋白基因的杂合突变体）中翅成虫盘的发育过程。微小动物在幼虫期表现出显著的发育延迟，但发育成基本正常的苍蝇，这表明存在一种机制，确保在异常延长的发育时间内组织生长健壮。令人惊讶的是，我们发现，细胞死亡和补偿性细胞增殖显着增加，在发展中的翅袋的分钟动物。通过抑制细胞死亡来阻断细胞周转导致形态缺陷，表明细胞周转在微小翅形态发生中起重要作用。我们的分析表明，微小的翼盘提高Wg的表达和JNK介导的Dilp8的表达，导致发育延迟，这两者都是必要的诱导细胞周转。此外，强迫增加Wg表达与蜕皮激素耗竭引起的发育延迟一起诱导非Minute动物翅袋中的细胞周转。我们的研究结果提出了一种新的范式，强大的协调组织生长的细胞周转，这是诱导时，发育时间轴被扭曲。动物的发育会受到各种刺激的干扰，如基因突变、环境波动和身体伤害。然而，即使在存在发育扰动的情况下，动物通常也能实现正常的组织生长和形态发生。果蝇微小突变体是果蝇核糖体蛋白基因的一系列突变体，表现出显著延长的幼虫期，但发育成基本正常的果蝇。我们发现了一个意想不到的大量细胞死亡和随后的补偿性细胞增殖发育中的翼盘的微小动物。这种“细胞周转率”是微小蝇正常翅形态发生所必需的。我们发现细胞更新是由翼袋中Wg表达升高和JNK介导的Dilp 8表达诱导的，从而导致发育延迟。事实上，通过使用wg启动子过表达Wg以及蜕皮激素耗尽引起的发育延迟，在非微小动物的翼盘中再现了细胞周转。我们的研究结果提出了一种通过细胞更新实现形态发生稳健性的新范式，可以通过创建灵活的细胞死亡和增殖平台来调整未来翼片中的细胞数量，确保在异常延长的幼虫期期间正常的翅膀生长。
Highly reproducible tissue development is achieved by robust, time-dependent coordination of cell proliferation and cell death. To study the mechanisms underlying robust tissue growth, we analyzed the developmental process of wing imaginal discs in Drosophila Minute mutants, a series of heterozygous mutants for a ribosomal protein gene. Minute animals show significant developmental delay during the larval period but develop into essentially normal flies, suggesting there exists a mechanism ensuring robust tissue growth during abnormally prolonged developmental time. Surprisingly, we found that both cell death and compensatory cell proliferation were dramatically increased in developing wing pouches of Minute animals. Blocking the cell-turnover by inhibiting cell death resulted in morphological defects, indicating the essential role of cell-turnover in Minute wing morphogenesis. Our analyses showed that Minute wing discs elevate Wg expression and JNK-mediated Dilp8 expression that causes developmental delay, both of which are necessary for the induction of cell-turnover. Furthermore, forced increase in Wg expression together with developmental delay caused by ecdysone depletion induced cell-turnover in the wing pouches of non-Minute animals. Our findings suggest a novel paradigm for robust coordination of tissue growth by cell-turnover, which is induced when developmental time axis is distorted. Animal development can be disturbed by various stimuli such as genetic mutations, environmental fluctuations, and physical injuries. However, animals often accomplish normal tissue growth and morphogenesis even in the presence of developmental perturbations. Drosophila Minute mutants, a series of fly mutants for a ribosomal protein gene, show significantly prolonged larval period but develop into essentially normal flies. We found an unexpected massive cell death and subsequent compensatory cell proliferation in developing wing discs of Minute animals. This ‘cell-turnover’ was essential for normal wing morphogenesis in Minute flies. We found that the cell-turnover was induced by elevated Wg expression in the wing pouch and JNK-mediated Dilp8 expression that causes developmental delay. Indeed, cell-turnover was reproduced in non-Minute animals’ wing discs by overexpressing Wg using the wg promoter together with developmental delay caused by ecdysone depletion. Our findings propose a novel paradigm for morphogenetic robustness by cell-turnover, which ensures normal wing growth during the abnormally prolonged larval period, possibly by creating a flexible cell death and proliferation platform to adjust cell numbers in the prospective wing blade.
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