Neuronal-Specific Iron Deficiency Dysregulates Mammalian Target of Rapamycin Signaling during Hippocampal Development in Nonanemic Genetic Mouse Models
Neuronal-Specific Iron Deficiency Dysregulates Mammalian Target of Rapamycin Signaling during Hippocampal Development in Nonanemic Genetic Mouse Models
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DOI：
10.3945/jn.112.168617
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发表时间：
2013-03-01
影响因子：
4.2
通讯作者：
Georgieff, Michael K.
中科院分区：
文献类型：
--
作者：
Fretham, Stephanie J. B.;Carlson, Erik S.;Georgieff, Michael K.
缺铁是全世界最常见的营养缺乏症，对婴儿、儿童和育龄妇女的影响不成比例。虽然缺铁性贫血通常与贫血(IDA)一起发生，但非贫血型缺铁性贫血在幼儿中的发病率是IDA的3倍，在妊娠并发症后的婴儿中也会发生。这两种情况都会对运动、社会情绪和认知行为产生负面影响，这表明除了贫血之外，铁在神经发育中也起着关键作用。在这里，铁在调节哺乳动物雷帕霉素信号靶(MTOR)信号通路(一种整合代谢供需以调节细胞生长和形态的激酶途径)中的特定作用被用2只海马体、锥体细胞特异的、非贫血的遗传小鼠模型ID：A CaMKIIαcre-loxP永久敲除二价金属转运体-1(DMT-1 CKO)和CaMKIIα-TTA驱动的可逆的、无功能的、显性的负转铁蛋白受体-1(DN TFR-1)的过度表达来研究。在这两个模型中，通过关键蛋白的磷酸化水平评估的mTOR活性在发育过程中被ID上调[S6K(Thr389)磷酸化在DMT-1 CKO和DN TFR-1模型中分别增加87%和57%；P<；0.05]。这一效应被证明是铁依赖的，因为出生后第21天的铁补充使可逆性糖尿病肾病TFR-1模型中mTOR活性正常化(与未复制的小鼠相比减少了62%；P<；0.05)。在永久性的DMT-1 CKO模型中，在铁的敏感期给予雷帕霉素抑制ID诱导的mTOR过度活动，改善了Morris水迷宫的表现，尽管仍在进行ID(DMT-1野生型和DMT-1 CKO小鼠在3天内达到标准，而赋形剂治疗的DMT-1 CKO小鼠需要4天；P<；0.05)。总之，这些发现暗示mTOR失调是伴随着早期生活的急性和持续性神经发育缺陷的一种细胞机制。2013年，143：260-266。
Iron deficiency (ID) is the most common nutrient deficiency worldwide, disproportionally affecting infants, children, and women of childbearing age. Although ID commonly occurs with anemia (IDA), nonanemic ID is 3 times more common than IDA in toddlers and also occurs in infants following gestational complications. Both conditions negatively affect motor, socio-emotional, and cognitive behaviors, suggesting that iron, apart from anemia, has a critical role in neurodevelopment. Here, the specific role of iron in regulation of mammalian target of rapamycin (mTOR) signaling (a kinase pathway that integrates metabolic supply and demand to regulate cell growth and morphology) was examined using 2 hippocampal, pyramidal cell-specific, nonanemic, genetic mouse models of ID: a CAMKII alpha cre-loxP permanent knockout of divalent metal transporter-1 (DMT-1 CKO) and a CAMKII alpha-tTA-driven reversible, overexpression of nonfunctional, dominant negative transferrin receptor-1 (DN TfR-1). In both models, mTOR activity, assessed by phosphorylation levels of key proteins, was upregulated during development by ID [S6K(Thr389) phosphorylation increased 87 and 57% in the DMT-1 CKO and DN TfR-1 models, respectively; P < 0.05]. This effect was shown to be iron-dependent, because iron repletion at postnatal d 21 normalized mTOR activity in the reversible DN TfR-1 model (62% reduction compared with unrepleted mice; P < 0.05). In the permanent DMT-1 CKO model, suppression of ID-induced mTOR hyperactivity by rapamycin administered during the sensitive period for iron improved Morris water maze performance despite ongoing ID (DMT-1 wild-type and DMT-1 CKO mice reached criterion in 3 d compared with 4 d necessary for vehicle-treated DMT-1 CKO mice; P < 0.05). Together, these findings implicate mTOR dysregulation as a cellular mechanism underlying the acute and persistent neurodevelopmental deficits that accompany early-life ID. J. Nutr. 143: 260-266, 2013.