细胞死亡中的模型系统——巨大的挑战

L. Schwartz
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引用次数: 0

摘要

1929年,诺贝尔奖得主、生理学家奥古斯特·克拉夫(August Krough)观察到:“对于许多问题,总会有一些或少数动物可供选择,它们是最方便研究的对象。”(克拉夫,1929)。这种对“模型系统”方法的欣赏被称为克拉夫原理,它已经成为基础生物学许多方面的基础,从使用鱿鱼巨大轴突来定义动作电位的离子基础到使用果蝇来解锁生物钟的分子基础。虽然许多研究人员的最终目标可能是更好地了解人类发育和/或发病机制,但哺乳动物系统的复杂性往往使直接分析具有挑战性。无脊椎动物和其他“更简单”的模型系统经常表现出夸大正常细胞过程的适应性,这使它们成为分析特定特征的有吸引力的工具。这种方法也被证明是研究细胞死亡的基础。术语“程序性细胞死亡”(PCD)(现在通常被称为“调节细胞死亡”,以区别于“意外细胞死亡”(Galluzzi等人,2018))是由Lockshin和Williams在1965年创造的,用于描述鳞翅目动物在变态结束时节间肌肉的精确时间损失(Lockshin和Williams, 1965)。这些巨细胞(每个约5毫米长,直径可达1毫米,取决于物种)在成蛾从上面的蛹角质层出现的同时启动PCD。很少有其他自然发生的PCD例子如此精确地定时或提供如此大量的清洁细胞材料用于分子和生化分析(例如,Tsuji et al., 2020)。然而,是另一种无脊椎动物模型——隐杆线虫,推动了细胞死亡领域从20世纪70年代和80年代的几十名研究人员的小型家庭手工业发展成为一个庞大的研究企业,在过去的30年里发表了56万多篇论文。秀丽隐杆线虫的一个独特特征使它成为一个如此吸引人的模型,它表现出“细胞一致性”,这意味着每个个体都有相同数量的体细胞。通过进行详细的谱系分析,Sulston和Horvitz描述了每个单细胞的身份和命运(Sulston和Horvitz, 1977)。对于大约20%的细胞,它们的命运是死亡,主要是通过凋亡。在进行这项工作的时候,人们还不太清楚发育过程中的PCD是否反映了多余/不必要细胞的简单浪费,邻近细胞的主动谋杀,或细胞自主自杀。霍维茨实验室利用一种巧妙的基因技巧,阻止垂死的细胞被吞噬,从而迅速被清除,证明细胞死亡的能力需要特定基因的活性,这些基因以细胞自主的方式起作用,因此代表了开放获取
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Model systems in cell death-grand challenge
In 1929, the Nobel Prize winning physiologist August Krough observed that “For a large number of problems there will be some animal of choice, or a few such animals, on which it can be most conveniently studied.” (Krogh, 1929). Known as the Krough Principal, this appreciation of a “model systems” approach has been foundational for many aspects of basic biology, from the use of the squid giant axon to define the ionic basis of the action potential to the use of the fruit fly to unlock the molecular basis of biological clocks. While the ultimate goal for many researchers may be to gain a better understanding of human development and/or pathogenesis, the complexity of mammalian systems often makes direct analyses challenging. Invertebrates and other “simpler”model systems often display adaptations that exaggerate normal cellular processes that make them attractive vehicles for the analysis of specific traits. This approach has also proven to be foundational for the study of cell death. The term “programmed cell death” (PCD) (now commonly referred to as “regulated cell death” to distinguish it from “accidental cell death” (Galluzzi et al., 2018)) was coined by Lockshin andWilliams in 1965 to describe the precisely timed loss of the intersegmental muscles of Lepidoptera at the end of metamorphosis (Lockshin and Williams, 1965). These giant cells (each of which is ~5 mm long and up to 1 mm in diameter depending on the species) initiate PCD coincident with the emergence of the adult moth from the overlying pupal cuticle. Few other naturally occurring examples of PCD are so exquisitely timed or offer such prodigious amounts of clean cellular material for molecular and biochemical analyses (e.g., Tsuji et al., 2020). However, it was another invertebrate model, the nematode Caenorhabditis elegans, that propelled the field of cell death from a small cottage industry with a few dozen investigators in the 1970s and 1980s into a massive research enterprise that has produced more than 560,000 publications during the past 30 years. One of the unique features of C. elegans that make it such an attractive model is that it displays “cell consistency”, meaning that every individual has the same number of somatic cells. By performing detailed lineage analyses, the identity and fate of every single cell was described by Sulston and Horvitz (Sulston and Horvitz, 1977). For about 20% of the cells, their fate is to die, primarily via apoptosis. At the time this work was conducted it was not well understood if PCD during development reflected the simple wasting away of surplus/unnecessary cells, active murder by neighboring cells, or cell-autonomous suicide. Using a clever genetic trick that prevented dying cells from being phagocytosed and thus rapidly removed, the Horvitz lab demonstrated that the ability of cells to die required the activity of specific genes that acted in a cell autonomous manner, and thus represented OPEN ACCESS
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