A gain-of-function screen to identify genes that reduce lifespan in the adult of Drosophila melanogaster.
A gain-of-function screen to identify genes that reduce lifespan in the adult of Drosophila melanogaster.
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DOI：
10.1186/1471-2156-15-46
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发表时间：
2014-04-16
期刊：
影响因子：
2.9
通讯作者：
Matsuno K
中科院分区：
文献类型：
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作者：
Nakayama M;Ishibashi T;Ishikawa HO;Sato H;Usui T;Okuda T;Yashiro H;Ishikawa H;Taikou Y;Minami A;Kato K;Taki M;Aigaki T;Gunji W;Ohtsu M;Murakami Y;Tanuma S;Tsuboi A;Adachi M;Kuroda J;Sasamura T;Yamakawa T;Matsuno K
一些证据表明，基因表达失调与糖尿病、阿尔茨海默病和其他疾病的危险因素有关，这些疾病在没有遗传疾病背景的健康成年人中偶尔发生。因此，我们对一些基因感兴趣，这些基因可能在个体生命的某些阶段正常表达，但在成年期表达不当会导致生理缺陷和疾病。我们试图通过在成年黑腹果蝇中任意错误表达特定基因来鉴定模式生物中的这些基因，使用了14,133个基因搜索线。我们确定了39个“寿命缩短基因”，当它们在成年期错误表达时，会使果蝇的寿命缩短到不到对照果蝇的30%。这些基因中约有一半具有已知与人类疾病有关的人类同源基因。对于大约四分之一的寿命缩短的基因，抑制细胞凋亡可以恢复因错误表达而缩短的寿命。我们确定了当这些基因在成年期特异性表达错误时导致寿命缩短的器官，并发现一些基因仅在特定的成年器官中错误表达时导致寿命缩短，而其他基因在各种器官中错误表达时可能导致寿命缩短。这一发现表明，组织特异性功能障碍可能与基因错误表达相关的寿命缩短有关。基因本体论分析表明，缩短寿命的基因偏向与发育相关的基因。我们确定了39个基因，当它们在成年期错误表达时，会缩短成年果蝇的寿命。抑制细胞凋亡只挽救了一小部分寿命缩短的基因的寿命。基因错误表达导致早期死亡的成体组织在缩短寿命的基因中有所不同。这些结果表明，错误表达导致寿命缩短的原因在基因之间是不同的。
Several lines of evidence associate misregulated genetic expression with risk factors for diabetes, Alzheimer’s, and other diseases that sporadically develop in healthy adults with no background of hereditary disorders. Thus, we are interested in genes that may be expressed normally through parts of an individual’s life, but can cause physiological defects and disease when misexpressed in adulthood. We attempted to identify these genes in a model organism by arbitrarily misexpressing specific genes in adult Drosophila melanogaster, using 14,133 Gene Search lines. We identified 39 “reduced-lifespan genes” that, when misexpressed in adulthood, shortened the flies’ lifespan to less than 30% of that of control flies. About half of these genes have human orthologs that are known to be involved in human diseases. For about one-fourth of the reduced-lifespan genes, suppressing apoptosis restored the lifespan shortened by their misexpression. We determined the organs responsible for reduced lifespan when these genes were misexpressed specifically in adulthood, and found that while some genes induced reduced lifespan only when misexpressed in specific adult organs, others could induce reduced lifespan when misexpressed in various organs. This finding suggests that tissue-specific dysfunction may be involved in reduced lifespan related to gene misexpression. Gene ontology analysis showed that reduced-lifespan genes are biased toward genes related to development. We identified 39 genes that, when misexpressed in adulthood, shortened the lifespan of adult flies. Suppressing apoptosis rescued this shortened lifespan for only a subset of the reduced-lifespan genes. The adult tissues in which gene misexpression caused early death differed among the reduced-lifespan genes. These results suggest that the cause of reduced lifespan upon misexpression differed among the genes.