JNK signaling triggers spermatogonial dedifferentiation during chronic stress to maintain the germline stem cell pool in the Drosophila testis.
JNK signaling triggers spermatogonial dedifferentiation during chronic stress to maintain the germline stem cell pool in the Drosophila testis.
复制标题
JNK信号传导会触发慢性应激过程中的精子去分化，以维持果蝇睾丸中的种系干细胞库。
DOI：
10.7554/elife.36095
复制
发表时间：
2018-07-09
期刊：
影响因子：
7.7
通讯作者：
Bach EA
中科院分区：
文献类型：
--
作者：
Herrera SC;Bach EA
干细胞衰竭是衰老的标志。在果蝇的睾丸中，来自精原细胞的去分化生殖系干细胞（GSCs）在寿命期间增加，导致去分化抵消老年雄性GSCs下降的模型。为了验证这一点，我们通过在精原细胞中错误表达分化因子bag of marbles （bam）来阻止去分化，同时对这些细胞进行谱系标记。引人注目的是，在正常条件下，在处女雄性中阻断bam谱系去分化对GSC池没有影响。然而，在雄性或具有挑战性的条件下，抑制bama谱系去分化显著减少GSCs的数量及其增殖和分化的能力。我们发现，在相同的睾丸中，bama谱系衍生的GSCs的增殖率明显高于兄弟GSCs。我们确定Jun n -末端激酶（JNK）活性是bamm谱系去分化所自主需要的。总的来说，我们表明去分化提供了一种在长期应激条件下维持种系和确保生育能力的机制。从心脏到大脑，我们的身体是由一组细胞组成的，这些细胞专门执行精确的任务。然而，某些器官承载着“干细胞”，它们可以变成任何类型的组织。例如，果蝇的睾丸含有生殖系干细胞；当其中一个细胞分裂时，子细胞保持非特化状态，而另一个细胞特化（或分化）成为精子。尽管以前认为，一个正在经历特化的细胞可以去分化，再次成为干细胞。随着有机体变老，干细胞变得“枯竭”：它们分裂得更少，失去了保持非特化的能力。因此，科学家们提出，去分化可能是一种补充日益减少的干细胞库，并抵御年龄影响的方法。然而，这一思路尚未在实验室中得到验证。在这里，Herrera和Bach试图通过创造两个雄性果蝇种群来验证这一假设。一个是基因完整的，另一个是经过修饰的，因此将成为精子细胞的细胞不能再去分化为生殖系干细胞。然后，这些昆虫被饲养在标准环境（食物充足但没有雌性）或压力环境（有或没有交配的饥饿期）中。实验表明，去分化对于维持一个强大的生殖系干细胞库是重要的，无论是在短期还是长期。然而，这只是在困难的环境下的情况；在较容易的生活条件下，去分化的能力并没有什么不同。此外，Herrera和Bach观察到，在果蝇的睾丸中，通过去分化获得的干细胞比“原始”干细胞分裂得更频繁。最后，进一步的分析强调了去分化所需的一系列基因。来自去分化细胞的干细胞以更高的速率分裂，这可能与各个领域的科学家有关。例如，这些知识可以帮助那些研究组织在损伤后如何再生的人，这是一个涉及去分化的过程。它也可以作为研究诱导多能干细胞的研究人员的一个警示故事——诱导多能干细胞是在实验室里通过特化细胞去分化而产生的。这一点可能特别重要，因为这些细胞有一天可能会被用于治疗帕金森病或阿尔茨海默病等疾病。
Exhaustion of stem cells is a hallmark of aging. In the Drosophila testis, dedifferentiated germline stem cells (GSCs) derived from spermatogonia increase during lifespan, leading to the model that dedifferentiation counteracts the decline of GSCs in aged males. To test this, we blocked dedifferentiation by mis-expressing the differentiation factor bag of marbles (bam) in spermatogonia while lineage-labeling these cells. Strikingly, blocking bam-lineage dedifferentiation under normal conditions in virgin males has no impact on the GSC pool. However, in mated males or challenging conditions, inhibiting bam-lineage dedifferentiation markedly reduces the number of GSCs and their ability to proliferate and differentiate. We find that bam-lineage derived GSCs have significantly higher proliferation rates than sibling GSCs in the same testis. We determined that Jun N-terminal kinase (JNK) activity is autonomously required for bam-lineage dedifferentiation. Overall, we show that dedifferentiation provides a mechanism to maintain the germline and ensure fertility under chronically stressful conditions. From the heart to the brain, our bodies are made of a collection of cells that are specialized to perform precise roles. Yet, certain organs host ‘stem cells’, which can become any kind of tissue. For example, the testicles of the fruit fly contain germline stem cells; when one of these cells divides, a daughter remains unspecialized, while the other specializes – or differentiates – to become sperm. Despite previous beliefs, a cell that is undergoing specialization can dedifferentiate to become a stem cell again. As the organism gets older, stem cells become ‘exhausted’: they divide less, and lose their ability to remain unspecialized. Scientists therefore proposed that dedifferentiation could be a way to replenish a dwindling pool of stem cells, and ward off the effects of age. However, this line of thought has not been tested in the laboratory. Here, Herrera and Bach tried to test this assumption by creating two populations of male fruit flies. One was genetically intact and the other was modified so that the cells that would become sperm cells could not dedifferentiate to become germline stem cells again. The insects were then raised in either a standard environment (plenty of food and no females) or in stressful conditions (periods of starvation with or without mating). The experiments showed that dedifferentiation was important to maintain a robust germline stem cell pool, both in the short and long term. This, however, was only the case in the difficult environment; the ability to dedifferentiate made no difference in the easier living conditions. In addition, Herrera and Bach observed that, in the flies’ testicles, stem cells obtained through dedifferentiation divided much more often than the ‘original’ stem cells. Finally, further analyses highlighted a series of genes that are required for dedifferentiation. That stem cells coming from dedifferentiated cells divide at a higher rate could be relevant to scientists across various fields. For example, this knowledge may help those who study how tissues regenerate after injury, a process that involves dedifferentiation. It also may be used as a cautionary tale for researchers who work on induced pluripotent stem cells – which are created in the laboratory by dedifferentiating specialized cells. This may be especially important because these cells could one day be put in patients to treat diseases such as Parkinson’s or Alzheimer’s.