Early-Life Neuronal-Specific Iron Deficiency Alters the Adult Mouse Hippocampal Transcriptome
Early-Life Neuronal-Specific Iron Deficiency Alters the Adult Mouse Hippocampal Transcriptome
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DOI：
10.1093/jn/nxy125
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发表时间：
2018-10-01
影响因子：
4.2
通讯作者：
Tran, Phu, V
中科院分区：
文献类型：
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作者：
Barks, Amanda;Fretham, Stephanie J. B.;Tran, Phu, V
背景资料：缺铁（ID）损害发育中的神经系统，包括海马体，导致尽管铁补充，但晚年仍有缺陷。铁依赖的分子变化驱动这些持久的赤字，以及早期铁补充的影响，是不完全了解。以前的研究已经利用母亲-胎儿ID贫血（IDA）的饮食模型来解决这些问题，然而，并发性贫血阻止描绘铁的具体role.Objective：本研究的目的是分离发育ID对成人海马基因表达的影响，并确定在非贫血海马神经元ID的小鼠模型中，铁补充是否逆转这些影响。通过使用Tet-OFF显性负转铁蛋白受体（DN-TFR 1）小鼠模型（该模型损害细胞铁摄取）生成非贫血性、海马特异性神经元ID。在出生后第21天（P21），在一组小鼠中用多西环素逆转海马ID，以创建2个实验组，慢性缺铁和以前缺铁的小鼠，将其与各自的多西环素治疗和未治疗的铁充足对照组进行比较。对来自成年雄性美洲驼的RNA进行测序。分析双端读段的差异表达。结果：与对照组相比，成年慢性缺铁性马勃中共有346个基因差异表达。关键神经发育途径中的ID失调基因，包括轴突导向、CDK 5、Ephrin受体、Rac和神经营养蛋白/Trk信号传导。铁在P21正常成人海马表达的198个基因，然而，基因参与cAMP反应元件结合蛋白（CREB）信号转导，神经认知，神经疾病仍然失调adultory.Conclusions：慢性ID在发展过程中，独立的贫血，改变成年小鼠海马转录组。在海马神经发育的一个已知的关键时期恢复铁状态不能完全使这些变化正常化，这表明需要额外的研究来确定铁治疗的最有效的时间轴，以及可以完全恢复ID诱导的分子变化的连续治疗，特别是在慢性ID流行的人群中。
Background: Iron deficiency (ID) compromises the developing nervous system, including the hippocampus, resulting in later-life deficits despite iron repletion. The iron-dependent molecular changes driving these lasting deficits, and the effect of early iron repletion, are incompletely understood. Previous studies have utilized dietary models of maternal-fetal ID anemia (IDA) to address these questions; however, concurrent anemia prevents delineation of the specific role of iron.Objective: The aim of the study was to isolate the effects of developmental ID on adult hippocampal gene expression and to determine if iron repletion reverses these effects in a mouse model of nonanemic hippocampal neuronal ID.Methods: Nonanemic, hippocampus-specific neuronal ID was generated by using a Tet-OFF dominant negative transferrin receptor (DN-TFR1) mouse model that impairs cellular iron uptake. Hippocampal ID was reversed with doxycycline at postnatal day 21 (P21) in a subset of mice to create 2 experimental groups, chronically iron-deficient and formerly iron-deficient mice, which were compared with their respective doxycycline-treated and untreated iron-sufficient controls. RNA from adult male hippocampi was sequenced. Paired-end reads were analyzed for differential expression. Differentially expressed genes were analyzed in Ingenuity Pathway Analysis.Results: A total of 346 genes were differentially expressed in adult, chronically iron-deficient hippocampi compared with controls. ID dysregulated genes in critical neurodevelopmental pathways, including axonal guidance, CDK5, Ephrin receptor, Rac, and Neurotrophin/Trk signaling. Iron repletion at P21 normalized adult hippocampal expression of 198 genes; however, genes involved in cAMP response element-binding protein (CREB) signaling, neurocognition, and neurologic disease remained dysregulated in adulthood.Conclusions: Chronic ID during development, independent of anemia, alters the adult mouse hippocampal transcriptome. Restoring iron status during a known critical period of hippocampal neurodevelopment incompletely normalized these changes, suggesting a need for additional studies to identify the most effective timeline for iron therapy, and adjunctive treatments that can fully restore ID-induced molecular changes, particularly in human populations in whom chronic ID is endemic.