Genetic interactions regulate hypoxia tolerance conferred by activating Notch in excitatory amino acid transporter 1-positive glial cells in Drosophila melanogaster.
Genetic interactions regulate hypoxia tolerance conferred by activating Notch in excitatory amino acid transporter 1-positive glial cells in Drosophila melanogaster.
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DOI：
10.1093/g3journal/jkab038
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发表时间：
2021-02-09
期刊：
影响因子：
--
通讯作者：
Haddad GG
中科院分区：
文献类型：
--
作者：
Zhou D;Stobdan T;Visk D;Xue J;Haddad GG
缺氧是许多人类疾病的关键病理因素，包括缺血性中风、心肌梗死和实体瘤。我们特别感兴趣的是细胞和分子机制，敏感性或耐受性低O2。已有研究表明Notch信号通路调节果蝇和人类的耐缺氧能力。然而，介导Notch赋予的缺氧耐受性的机制在很大程度上是未知的。在这项研究中，我们描绘了这种耐缺氧表型的进化保守机制。我们确定了一组保守基因的作用，这些基因是从对耐缺氧的黑腹果蝇种群和生活在世界高海拔地区的人类高地人（西藏人，安第斯人和安第斯人）的比较基因组分析中获得的。我们开发了一种新的双UAS/Gal 4系统，使我们能够激活Eaat 1阳性神经胶质细胞中的Notch信号传导，这显著增强了黑腹果蝇的缺氧耐受性，同时，敲低了同一组神经胶质细胞中的候选基因。使用该系统，我们发现Notch信号传导与bnl（成纤维细胞生长因子）、croc（叉头转录因子C）或Mkk 4（促分裂原活化蛋白激酶激酶4）之间的相互作用对于缺氧耐受性是重要的，至少部分地通过调节缺氧条件下的神经元发育和存活。由于这些遗传机制在进化上是保守的，因此这组基因可以作为开发治疗策略的新靶点，并且具有很强的潜力被翻译到人类中以治疗/预防缺氧相关疾病。
Hypoxia is a critical pathological element in many human diseases, including ischemic stroke, myocardial infarction, and solid tumors. Of particular significance and interest of ours are the cellular and molecular mechanisms that underlie susceptibility or tolerance to low O2. Previous studies have demonstrated that Notch signaling pathway regulates hypoxia tolerance in both Drosophila melanogaster and humans. However, the mechanisms mediating Notch-conferred hypoxia tolerance are largely unknown. In this study, we delineate the evolutionarily conserved mechanisms underlying this hypoxia tolerant phenotype. We determined the role of a group of conserved genes that were obtained from a comparative genomic analysis of hypoxia-tolerant D.melanogaster populations and human highlanders living at the high-altitude regions of the world (Tibetans, Ethiopians, and Andeans). We developed a novel dual-UAS/Gal4 system that allows us to activate Notch signaling in the Eaat1-positive glial cells, which remarkably enhances hypoxia tolerance in D.melanogaster, and, simultaneously, knock down a candidate gene in the same set of glial cells. Using this system, we discovered that the interactions between Notch signaling and bnl (fibroblast growth factor), croc (forkhead transcription factor C), or Mkk4 (mitogen-activated protein kinase kinase 4) are important for hypoxia tolerance, at least in part, through regulating neuronal development and survival under hypoxic conditions. Becausethese genetic mechanisms are evolutionarily conserved, this group of genes may serve as novel targets for developing therapeutic strategies and have a strong potential to be translated to humans to treat/prevent hypoxia-related diseases.
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DOI：
10.1534/g3.112.003681
发表时间：
2012-10
期刊：
G3 (Bethesda, Md.)
影响因子：
--
作者：
Azad P;Zhou D;Zarndt R;Haddad GG
通讯作者：
Haddad GG
DOI：
10.1007/978-3-030-34436-8_3
发表时间：
2020-01-01
期刊：
NOTCH SIGNALING IN EMBRYOLOGY AND CANCER: NOTCH SIGNALING IN EMBRYOLOGY
影响因子：
--
作者：
Bahrampour, Shahrzad;Thor, Stefan
通讯作者：
Thor, Stefan
影响因子：
3.5
作者：
Besson, MT;Soustelle, L;Birman, S
通讯作者：
Birman, S
影响因子：
11.2
作者：
Comerford, KM;Cummins, EP;Taylor, CT
通讯作者：
Taylor, CT
影响因子：
4.2
作者：
GIBSON, G
通讯作者：
GIBSON, G