“Regulation of iron metabolism: Deciphering the biological functions of the iron responsive element of divalent-metal transporter 1”

铁是许多新陈代谢过程所必需的辅助因素，但过量存在时是有毒的，铁代谢失衡是一些最常见的疾病的原因。在过去的二十年里，广泛的研究已经发现了铁稳态的关键分子。在这些分子中，跨膜质子偶联铁导入蛋白DMT1(二价金属转运蛋白1)被证明对膳食铁的同化以及红系细胞对铁的获取是必不可少的。为了防止铁缺乏和铁过剩，必须非常严格地控制DMT1的表达。在哺乳动物中，细胞铁稳态是由铁调节蛋白(IRP)-1和-2协调的，它们通过与被称为铁反应元件(IRE)的顺式调节RNA结构结合来控制铁代谢mRNAs的命运。DMT1mRNA在其3‘非翻译区带有一个单一的非规范IRE，因此可能受到IRPS的调控。然而，到目前为止，缺乏合适的动物模型阻碍了对DMT1IRE在体内功能的更好理解。为了填补这一空白，我们创建了一个选择性破坏DMT1 3‘IRE的小鼠系，这是第一个对此类RNA基序进行靶向突变的动物模型。我们的初步工作表明，DMT1的IRE对于正常的红细胞生成和防止在标准实验室条件下维持的年轻成年小鼠的全身铁超载是必需的。基于对组织和血清学铁代谢参数、血液学参数和铁代谢基因的分子分析的详细探索，我们建议确定在年轻成年DMT1突变小鼠中观察到的铁失衡的原因。此外，我们将研究与明显的铁代谢特征相关的其他生命阶段的铁表型，更准确地说，是在围产期小鼠有高铁需求并依赖母乳的时候，以及在高铁储存和正常饮食的老年动物中。此外，我们将评估DMT1的IRE是否以及如何影响铁稳态机制对膳食铁供应和应激性红细胞生成条件的波动的适应性反应。通过这项工作，我们希望揭示细胞中一个重要的铁转运蛋白的新方面，并加强我们对转录后调控机制在代谢调节中的作用的理解。

Iron is a co-factor required for numerous metabolic processes but toxic when present in excess, and imbalances of iron metabolism account for some of the most common diseases. Extensive research during the last two decades has uncovered key molecules of iron homeostasis. Among those molecules, the transmembrane proton-coupled iron importer DMT1 (divalent metal transporter 1) was shown to be essential for dietary iron assimilation as well as for iron acquisition by erythroid cells. To prevent both iron insufficiency and excess, the expression of DMT1 must be controlled very tightly. In mammals, cellular iron homeostasis is orchestrated by the iron regulatory proteins (IRP)-1 and -2, which control the fate of iron metabolism mRNAs by binding to cis-regulatory RNA structures named iron-responsive elements (IRE). The DMT1 mRNA bears a single, non-canonical IRE in its 3’ untranslated region, and is thus potentially regulated by the IRPs. However, the lack of adequate animal models has so far hampered a better comprehension of the in vivo functions of the DMT1 IRE. To fill this gap, we have created a mouse line with selective disruption of the 3’IRE of DMT1, which represents the first animal model with targeted mutagenesis of such RNA motifs. Our preliminary work indicates that the IRE of DMT1 is required for normal erythropoiesis and to prevent systemic iron overload in young adult mice maintained under standard laboratory conditions. Based on a detailed exploration of tissular and serological iron metabolism parameters, a study of hematological parameters, and a molecular analysis of iron metabolism genes, we propose to determine the cause of the iron imbalance observed in young adult DMT1-mutant mice. In addition, we will examine the iron phenotype at other stages of life asociated with distinct iron metabolism characteristics, more precisely during perinatal life when mice have high iron needs and rely on maternal milk, and in aged animals with high iron stores and feeding on a normal diet. Furthermore, we will assess whether and how the IRE of DMT1 impacts on the adaptative responses of the iron homeostasis machinery to fluctuations in dietary iron availability and in conditions of stress erythropoiesis. With this work we wish to unveil new facets of an essential iron transporter in the cell, and enhance our understanding of the role of posttranscriptional control mechanisms in metabolic regulations.