Iron Delivery in the Developing Kidney

妊娠期缺铁是世界上最常见的微量营养素缺乏症，影响多达20亿人。妊娠期缺铁会增加胚胎死亡、早产和低出生体重婴儿的风险，这突出了了解所需铁量如何传递到胚胎以预防出生缺陷的重要性。 发育中的肾脏需要足够的铁，以便在怀孕期间和出生后早期获得最佳器官形成。铁是整个肾脏形态发生所必需的，包括在后肾间充质转化为上皮细胞期间，在输尿管芽的分支期间，以及在出生后完成肾小球形成期间。缺铁会减少肾单位数量，导致发育不全和高血压，从而增加成年后肾衰竭和心血管疾病的风险。然而，铁从胎盘运输到发育中器官（包括肾脏）的不同细胞谱系的机制一直是一个“黑匣子”，因此在了解缺铁对器官发生的影响方面几乎没有进展，几乎没有文献。 目前的铁贩运模式来自成人研究。这些研究揭示了所谓的铁循环的分子机制，但令人惊讶的是，其主要成分（转移，转移受体1 [Tfr 1]，二价金属转运蛋白1[DMT 1]，Steap 3，TIM）的缺失在胚胎中产生的表型比这些蛋白质的普遍存在及其在物种中的保守性所预测的要有限得多。因此，它仍然不清楚是否输尿管芽和间充质在发展中的肾脏获得铁从不同的来源，是否铁的交付是“细胞自主”或相互诱导也包括交换间室的铁，以及是否铁缺乏失调不同细胞系的器官发生不同？ 在这个建议中，我们确定铁运输过程，诱导真实的生长和发育的遗传解剖功能的中央铁传递途径，Tf-Tfr 1，在发展中的肾脏。最初的数据出乎意料地提出了以下假设，我们在这里测试：这些是（1）细胞特异性，和（2）Tf-Tfr 1的时间特异性需求，（3）由Tfr 1介导的经典细胞自主机制，但另外也可能是细胞非自主途径，（4）非Tf铁供体的活性，包括涉及铁蛋白的新途径和（5）独特的铁转运蛋白的活性，其对于将Tf铁转运到发育中的肾脏的胞质溶胶是足够的和必需的。这些假设确定和测试新的，组织特异性和阶段特异性的铁传递机制，暗示复杂和高度调节的机制同步细胞需要与铁捕获。我们认为，这些途径可能是妊娠期缺铁的目标，这是众所周知的限制肾脏的生长和发育。

DESCRIPTION (provided by applicant): Iron deficiency in pregnancy is the most common micronutrient deficiency in the world, affecting as many as 2 billion people. Iron deficiency in pregnancy increases the risk for embryonic mortality, a preterm delivery and low birth weight baby, which highlights the importance of understanding how the required quantity of iron is delivered to the embryo for the prevention of birth defects. The developing kidney requires sufficient iron for optimal organogenesis during pregnancy and in the early postnatal period. Iron is required throughout kidney morphogenesis, including during conversion of the metanephric mesenchyme into epithelia, during the branching of the ureteric bud, and during the postnatal completion of glomerulogenesis. Iron deficiency reduces nephron number and results in hypoplasia and hypertension, which increases the risk of renal failure and cardiovascular diseases in adult life. However, the mechanism by which iron traffics from the placenta to different cell lineages in developing organs including kidney has been a "black box" and as a result there have been few advances and almost no literature in understanding the impact of iron deficiency on organogenesis. The current paradigm of iron trafficking derives from studies in the adult. These studies have revealed the molecular mechanisms underlying the so-called iron cycle, but surprisingly the deletion of its main components (transferring, transferring receptor1[Tfr1], divalent metal transporter 1[DMT1], Steap3, TIM) has produced much more limited phenotypes in the embryos than might have been predicted by the ubiquity of these proteins, and their conservation among species. Hence it remains unclear whether the ureteric bud and mesenchyme in the developing kidney obtain iron from different sources, whether iron delivery is "cell autonomous" or does reciprocal induction also include the exchange of iron between compartments, and whether iron deficiency dysregulates organogenesis of different cell lineages differently? In this proposal, we identify iron trafficking processes that induce real growth and development by genetically dissecting the functions of the central iron delivery pathway, Tf-Tfr1, in the developing kidney. The initial data unexpectedly suggested the following hypotheses, which we test here: these are (1) a cell specific, and (2) a temporally specific requirement for Tf-Tfr1, (3) a classical cell autonomous mechanism mediated by Tfr1, but additionally the possibility of a cell non-autonomous pathway as well, (4) the activity of non-Tf iron donors, including a novel pathway involving ferritin and (5) the activity of a unique iron transporter that is both sufficient and necessary to transfer Tf iron to the cytosol of the developing kidney. These hypotheses identify and test novel, tissue specific, and stage specific mechanisms of iron delivery, implicating that complex and highly regulated mechanisms synchronize cell need with iron capture. We suggest that these pathways are likely to be the target of iron deficiency in pregnancy, which is known to limit kidney growth and development.