Neuroglobin-deficiency exacerbates Hif1A and c-FOS response, but does not affect neuronal survival during severe hypoxia in vivo.
Neuroglobin-deficiency exacerbates Hif1A and c-FOS response, but does not affect neuronal survival during severe hypoxia in vivo.
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DOI：
10.1371/journal.pone.0028160
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Hay-Schmidt A
中科院分区：
文献类型：
--
作者：
Hundahl CA;Luuk H;Ilmjärv S;Falktoft B;Raida Z;Vikesaa J;Friis-Hansen L;Hay-Schmidt A
神经球蛋白（Neuroglobin, Ngb）是一种体外结合氧的神经元特异性球蛋白，在大脑缺氧和缺血损伤后的神经元存活中起关键作用。在这里，我们研究了Ngb基因缺乏（Ngb-null）小鼠急性和长期缺氧后神经元存活是否需要Ngb。此外，为了评估Ngb缺乏是否会影响缺氧依赖的基因调控，我们使用Affymetrix小鼠基因1.0 ST阵列对差异基因表达进行了转录组范围的分析。通过一种新的数据分析方法估计差分表达式，该方法将非参数统计推断直接应用于探针水平测量。ngb缺失小鼠按预期比例出生，外观、家笼行为、繁殖和寿命均正常。Ngb缺乏对神经元数量没有影响，在缺氧48小时后，野生型（wt）和无Ngb小鼠的内源性表达Ngb神经元的替代标志物染色呈阳性。然而，在ngb缺失的小鼠中，c-FOS蛋白（一种反映神经元激活的即时早期转录因子）的表达和Hif1A mRNA的表达都出现了缺氧依赖性的增加。大规模基因表达分析发现，ngb缺失小鼠急性缺氧后糖酵解途径基因的表达存在差异，但在wts中没有差异。在两种基因型中，染色质重塑、mRNA加工和能量代谢途径的广泛缺氧依赖调控都是明显的。根据这些结果，Ngb的丢失似乎不太可能影响体内缺氧时神经元的活力。相反，ngb缺乏似乎增强了Hif1A和c-FOS蛋白的缺氧依赖性反应，同时也改变了糖酵解途径的转录调节。差异基因表达的生物信息学分析得出了新的预测，表明染色质重塑和mRNA代谢是适应长时间缺氧的关键调控机制之一。
Neuroglobin (Ngb), a neuron-specific globin that binds oxygen in vitro, has been proposed to play a key role in neuronal survival following hypoxic and ischemic insults in the brain. Here we address whether Ngb is required for neuronal survival following acute and prolonged hypoxia in mice genetically Ngb-deficient (Ngb-null). Further, to evaluate whether the lack of Ngb has an effect on hypoxia-dependent gene regulation, we performed a transcriptome-wide analysis of differential gene expression using Affymetrix Mouse Gene 1.0 ST arrays. Differential expression was estimated by a novel data analysis approach, which applies non-parametric statistical inference directly to probe level measurements. Ngb-null mice were born in expected ratios and were normal in overt appearance, home-cage behavior, reproduction and longevity. Ngb deficiency had no effect on the number of neurons, which stained positive for surrogate markers of endogenous Ngb-expressing neurons in the wild-type (wt) and Ngb-null mice after 48 hours hypoxia. However, an exacerbated hypoxia-dependent increase in the expression of c-FOS protein, an immediate early transcription factor reflecting neuronal activation, and increased expression of Hif1A mRNA were observed in Ngb-null mice. Large-scale gene expression analysis identified differential expression of the glycolytic pathway genes after acute hypoxia in Ngb-null mice, but not in the wts. Extensive hypoxia-dependent regulation of chromatin remodeling, mRNA processing and energy metabolism pathways was apparent in both genotypes. According to these results, it appears unlikely that the loss of Ngb affects neuronal viability during hypoxia in vivo. Instead, Ngb-deficiency appears to enhance the hypoxia-dependent response of Hif1A and c-FOS protein while also altering the transcriptional regulation of the glycolytic pathway. Bioinformatic analysis of differential gene expression yielded novel predictions suggesting that chromatin remodeling and mRNA metabolism are among the key regulatory mechanisms when adapting to prolonged hypoxia.
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影响因子：
2.9
作者：
Hundahl, Christian Ansgar;Allen, Gregg C.;Hay-Schmidt, Anders
通讯作者：
Hay-Schmidt, Anders
影响因子：
14.9
作者：
Benita Y;Kikuchi H;Smith AD;Zhang MQ;Chung DC;Xavier RJ
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Xavier RJ
影响因子：
11.2
作者：
Chen, Haobin;Yan, Yan;Costa, Max
通讯作者：
Costa, Max
DOI：
10.1016/s0034-5687(01)00306-1
发表时间：
2001-11-15
期刊：
RESPIRATION PHYSIOLOGY
影响因子：
--
作者：
Erecinska, M;Silver, IA
通讯作者：
Silver, IA
DOI：
10.1097/01.wcb.0000141558.40491.75
发表时间：
2004-12-01
影响因子：
6.3
作者：
Hedtjarn, M;Mallard, C;Hagberg, H
通讯作者：
Hagberg, H