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Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

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Plant Metal Transporters with Homology to Proteins of the NRAMP Family

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Plants need metal transporters to fulfill many essential functions ranging from metal absorption to metal sequestration and storage. In some cases, plants also have to deal with toxic heavy metals such as cadmium, lead and mercury or toxic excess of essential metals. This chapter focuses on our knowledge of the properties and functions of plant metal transporters with homology to the Natural Resistance Associated Macrophage Protein 1 (NRAMP1). The plant NRAMP family is now well documented in both plant genomic and plant EST databases, demonstrating that genes from this family are present in virtually all plants studied at the molecular level. Plant NRAMP genes complement yeast mutants deficient in the uptake of several metals, including iron, manganese and zinc, demonstrating their conserved function as metal transporters among all kingdoms. The elucidation of the function of NRAMP genes in plant cells is an emerging field supported by reverse genetic studies on NRAMP knock-out plants and systematic tissue and subcellular localization using promoter reporter gene fusion and transporter-green fluorescent protein fusion. In plants, several NRAMP genes are up-regulated under Fe starvation, indicating a function in Fe nutrition. NRAMP proteins likely localize on intracellular membranes such as the plastid envelope and the vacuolar membrane. Over-expression or disruption of NRAMP genes in Arabidopsis leads to changes in Fe or Cd sensitivity. The plant NRAMP family raises the question of the importance of dynamic metal compartmentalization in plant cells.


Plants need metal transporters to fulfill many essential functions ranging from metal absorption to metal sequestration and storage.1 Plant roots represent the main site for the primary uptake of metals from soils to the food chain. Therefore the uptake and trafficking of beneficial as well as toxic heavy metals by plants determines to a large extent the quality of food. Because the abundance and the bioavailability of micronutrient metals can be very limiting in some soils, plants have developed efficient absorption strategies. These strategies have been best studied in the case of iron (Fe). To take up iron, plants use two distinct strategies, the first one that is used by all plants except grasses is based on the reduction of iron from ferric chelates at the root surface and subsequent uptake by a ferrous iron uptake transporter.2 This strategy is analogous to the mechanism of iron uptake in yeast.3 The second one is based on the release of Fe chelating molecules called phytosiderophores in the soil solution surrounding the root.4 Then, specific transporters catalyze the uptake of ferric iron phytosiderophore complexes into the root cells.5 This strategy is analogous to the iron uptake strategy by many soil and pathogen bacteria.6,7

In addition to metal absorption, plants also need to be able to transport transition metals to the growing organs and to the cell compartments where they are necessary. A fine control of metal concentrations is required in chloroplasts in photosynthetic tissues, where metals play essential roles in photosynthesis but can cause serious oxidative damage. In some cases, plants also have to deal with toxic heavy metals such as cadmium, lead and mercury or toxic excess of essential metals. In this case, transporters can function either in excluding metals at the root or sequestering metals in some cell compartments such as the vacuole.

Thus, it is not surprising that the analysis of the Arabidopsis genome has uncovered the existence of several large families of metal transporter genes. These families include zinc and iron transporters ZRT1-IRT1 like proteins (ZIP, 15 members in Arabidopsis genome), Cu and Cd transporting ATPases (7 members), Zn and Cd transporting Cation Diffusion Facilitator (CDF, 8 members), copper transporters (CTR, 6 members), and NRAMP homologues810 (http://www.cbs.umn.edu/arabidopsis/). In addition, members of the vacuolar cation proton exchanger (CAX) and of the ABC transporter family are involved in metal homeostasis in plant cells.11,12

Individual metal transporters from several of the above families have been implicated in a variety of functions at the cellular and plant levels. IRT1, a member of the ZIP family was shown to encode the primary uptake transporter for Fe, Mn, Zn and Co uptake from the soil through the plasma membrane of root epidermal cells.13,14 RAN1, a member of the CuATPase family in Arabidopsis with homology to the Menkes and Wilson diseases genes,15 is important for the loading of copper on Cu containing proteins such as the ethylene receptor.16,17 ZAT1, a member of the CDF family was shown to increase Zn tolerance when over-expressed in plants.18 This tolerance is likely the result of an increased sequestration in the vacuolar compartment.

This chapter focuses on our knowledge of the properties and functions of plant homologues of the Natural Resistance Associated Macrophage Protein 1 (NRAMP1). After NRAMP1 was characterized as a resistance gene to intracellular pathogens in mouse,19 homologues of NRAMP1 were characterized in plants. Belouchi and collaborators have detected the presence of several genes of the NRAMP family among rice ESTs and cloned corresponding cDNAs.20,21 However, the understanding of NRAMP functions in plants remained limited. The plant NRAMP family is now well documented in both plant genomic and plant EST databases, demonstrating that genes from this family are present in virtually all plants studied at the molecular level. Plant NRAMP genes complement yeast mutants deficient in the uptake of several metals demonstrating their conserved function as metal transporters among all kingdoms.22,23 In addition, Arabidopsis harbor EIN2, which contains a NRAMP homologous domain fused to a soluble domain and was initially identified by genetic studies as a gene required for Arabidopsis sensitivity to the plant hormone ethylene.24,25 The elucidation of the function of NRAMP genes in plant cells is an emerging field supported by reverse genetic studies on NRAMP knock-out plants and the systematic tissue and subcellular localization of plant membrane proteins using promoter reporter gene fusion and transporter-green fluorescent protein fusion. This study is complex because of the rather high number of NRAMP genes present in plant genomes, which may cause functional redundancy within the family.

Genomic Analysis of the NRAMP Family in Plant Species

A database search for NRAMP homologous genes in plant species identifies a large number of genes. Overall the plant NRAMP proteins show high amino acid sequence conservation with NRAMP from other kingdoms. For instance, Arabidopsis NRAMP proteins share between 40 and 50% amino acid sequence identity with mouse NRAMP1 and about 30% identity with the yeast NRAMP SMF1. Even higher sequence conservation is found in the predicted transmembrane domains (TMs) and the bacterial Consensus Transport Sequence found between TM8 and TM9.26

Interestingly NRAMP genes are distributed among all plant families. They are present both in grasses and nongraminaceous species. These two groups of plants use different strategies to take up iron (Fe) from the soil solution.2 The occurrence of NRAMP genes in these two groups of plants suggests a general function in metal homeostasis distinct from the initial steps of metal uptake from the soil solution.

Another feature of plant NRAMP genes is the relatively high number of homologues per species. The Arabidopsis genome encodes six NRAMP homologues, in addition to EIN2, whereas yeast and mouse genomes encode only three and two NRAMP genes, respectively. A similar situation is found in rice: the complete genome sequence of rice also contains at least seven distinct genes encoding NRAMP homologous proteins27 (http://www.cbs.umn.edu/rice/). In addition, we have identified several ESTs with homology to NRAMP in species as diverse as Medicago truncatula, soybean, cotton, tomato, pine tree, maize and barley. However, it is not possible at the moment to determine how many NRAMP genes the genomes of these plant species contain.

Examination of the phylogenetic tree of plant NRAMP proteins reveals the existence of two distinct subfamilies independent from the clusters formed by animal, bacterial and yeast NRAMP sequences: the group I contains among others AtNRAMP1 (Arabidopsis), LeNRAMP1 (tomato) and OsNRAMP1 (rice) and the group II contains AtNRAMP2 and OsNRAMP2 (Fig. 1). Whereas AtNRAMP2, 3, 4 and 5 from the group II share between 67 and 75% identity, they share only 33 to 37% identity with AtNRAMP1 and 6 from group II. In addition to the divergence in the primary amino acid sequence between genes from group I and II, they display striking differences in the gene organization: genes from the group I such as AtNRAMP1 and AtNRAMP6 are highly fragmented with as many as 12 introns, whereas genes from the group II such as AtNRAMP2, 3, 4 and 5 have only 2 to 3 introns located at conserved positions (Fig. 2). This sequence divergence suggests early evolutionary separation between the two groups of plant NRAMPs. Although both groups are nuclear encoded one group could derive from the eucaryotic branch whereas the other would originate from endosymbiotic organites such as mitochondria or plastids. Group II appears to be more closely related to known animal NRAMP homologues than group I. Phylogenetic analyses of the translated EST sequences from Medicago truncatula, Glycine max, cotton and tomato reveal that all these species harbor NRAMP genes from group I and group II. This suggests that both group I and group II are required for proper metal homeostasis in plants.

Figure 1. Phylogenetic tree of NRAMP genes.

Figure 1

Phylogenetic tree of NRAMP genes. Nramp homologous genes: EIN2, AtNRAMP1 (AF 165125), AtNRAMP2 (AF 141204), AtNRAMP3 (AF202539), AtNRAMP4 (AF202540), AtNRAMP5 (At4g18790) and AtNRAMP6 (At1g15960) from Arabidopsis; OsNRAMP1 (L41217), OsNRAMP2 (L81152), (more...)

Figure 2. Genomic organization of Arabidopsis NRAMP genes.

Figure 2

Genomic organization of Arabidopsis NRAMP genes. Alignment between the coding sequence and the genomic sequence of Arabidopsis NRAMP genes was performed to determine the position of introns (black box). The grey box indicate a predicted intron that was (more...)

In addition to the NRAMP genes, the Arabidopsis genome encodes the EIN2 protein that contains an amino-terminal domain with clear homology to NRAMP proteins. However the NRAMP domain of EIN2 is divergent from any other known NRAMP sequence and shares only 17 to 20% identity with other Arabidopsis NRAMP homologs. This domain is fused to a “signaling” domain, which does not bear any significant homology with any protein identified so far. The analysis of ein2 mutants has shown that EIN2 functions in multiple signaling pathways regulating the transduction the plant gaseous hormone ethylene, the sensitivity to jasmonate, and resistance to pathogens.25

Functional Characterization of NRAMP Metal Transport Properties in Heterologous Expression Systems

Starting with SMF1, NRAMP proteins have been shown to function as metal transporters. SMF1 was first identified as a component of the Mn uptake system in yeast.28 Following, DCT1/DMT1/NRAMP2 was identified as the main Fe uptake transporter in mammalian duodenum and shown to transport a range of heavy metals.29 An emerging concept is that NRAMP genes encode transition metal transporters with broad specificity. The metal transport function of plant NRAMP proteins has been demonstrated by complementation of yeast mutants impaired in metal uptake. OsNRAMP1, AtNRAMP1, 3, 4 and 5 can complement Fe uptake in the yeast double knockout strain fet3fet4.30,31 which is defective in both high and low affinity iron uptake systems (Table 1).22,23,32 In contrast, OsNRAMP2 and AtNRAMP2 fail to complement this strain.22 The ability of some plant NRAMP homologues to transport other metals has also been tested. AtNRAMP1, 3, 4 and 5 complement the phenotype of smf1,28 which is defective in manganese uptake.23,32 (Table 1). In addition, AtNRAMP4, but not AtNRAMP1 or 3 complements the growth of zrt1zrt2 yeast.33,34 in which low and high affinity Zn transporters have been disrupted (Table 1, S. Thomine unpublished). The complementation of the yeast plasma membrane uptake systems for Fe, Mn and Zn requires strong constitutive expression of the plant NRAMP genes, suggesting that yeast cells express plant NRAMP proteins at the plasma membrane with low efficiency. Furthermore, expression of plant AtNRAMP1, 3 and 4 genes in wild type yeast increase their sensitivity to the toxic metal cadmium.23 This supports the idea that in addition to essential metals, plant NRAMP transporters can also transport toxic metals. Altogether, these results show that plant NRAMP encode metal transporters able to transport several different transition metals.

Table 1. Complementation of yeast metal uptake mutants by plant NRAMP genes.

Table 1

Complementation of yeast metal uptake mutants by plant NRAMP genes.

Interestingly, the different NRAMP transporters tested do not transport the same range of metals. For example, although AtNRAMP1, 3 and 4 all induce the same level of Cd hypersensitivity, AtNRAMP3 and 4 complement fet3fet4 with a greater efficiency than AtNRAMP1 and, AtNRAMP4 is the only one among the NRAMP genes we tested which is able to complement zrt1zrt2 growth on low zinc level.23 The transport selectivity of plant NRAMP protein seems independent of whether they belong to group I or to group II in the phylogenetic tree (Table 1, Fig. 1). Although other plant NRAMP genes have been shown to encode metal transporters, no metal transport function could be demonstrated for EIN2. It has been proposed that EIN2 could function as a metal sensor in plant cells.35 In the future it will be interesting to determine the complete substrate range for each NRAMP transporter and to identify the structural features underlying the differences in selectivity. The transport mechanism that plant NRAMP use also remains to be determined. Based on the strong pH sensitivity of the complementation of fet3fet4 phenotype by AtNRAMP3 and 4,23 it has been hypothesized that the metals might be cotransported with protons, as demonstrated for mammalian NRAMP2/DCT1/DMT1 and yeast SMF1.29,36 Attempts to express AtNRAMP3 and 4 in Xenopus oocytes to analyze the transport mechanism in more detail did not allow to record any significant metal currents (S. Thomine and J. Schoeder, unpublished).

NRAMP Gene Expression Pattern and Regulation in Plants

The expression of plant NRAMP genes has been studied by Northern blot and promoter-reporter gene fusions. In contrast to the metal transporter genes from the ZIP family, IRT1 and IRT2, which are strictly root specific, several plant NRAMP genes are expressed both in roots and shoots (Table 2). Some members of the family are preferentially expressed in the roots (AtNRAMP1 and 2, LeNRAMP1 and 3 and OsNRAMP1) and others in the shoots (AtNRAMP3 and 4, OsNRAMP2 and 3). The preferential expression of plant NRAMP genes in the roots or shoots is independent of whether they belong to group I or to group II of the phylogenetic tree. For instance, OsNRAMP3 and AtNRAMP1 and LeNRAMP1 all belong to group I. OsNRAMP3 expression is stronger in the shoots whereas AtNRAMP1and LeNRAMP1 expressions are stronger in the roots21,22,37 (Table 2, Fig. 1). The expression of AtNRAMP5 is restricted to the reproductive organs in Arabidopsis.32 Consistent with its expression pattern restricted to root epidermal cells, IRT1 encodes the primary metal uptake transporter driving influx of iron from the soil into the root cells.14 In contrast the expression of NRAMP genes in both roots and shoots suggests that they participate in metal homeostasis in all plant organs.

Table 2. Expression pattern and regulation of plant NRAMP genes.

Table 2

Expression pattern and regulation of plant NRAMP genes.

NRAMP2/DMT1/DCT1 plays an important role in iron uptake and recycling in mammalian cells. The expression of some NRAMP genes from Arabidopsis and rice can rescue the growth on low iron medium of the yeast mutant fet3fet4, which is defective in iron uptake (Table 1). To investigate the possible function of NRAMP in iron homeostasis in plants, several studies have tested the regulation of NRAMP expression under iron starvation conditions. In Arabidopsis, several NRAMP homologues are up-regulated in iron deficient plants. AtNRAMP1, AtNRAMP3 and AtNRAMP4 that can complement the Fe uptake mutant in yeast are up-regulated in the root system under iron starvation.22,23 This is a good indication that they function in iron homeostasis in plants. LeNRAMP1, the tomato homologue of AtNRAMP1 is also up-regulated under iron starvation.37 However, the expression of LeNRAMP3, the closest homologue of AtNRAMP3 in tomato, is insensitive to the iron nutrition status of the tomato (Fig. 1, Table 2).37

Interestingly, LeNRAMP1 activation under iron starvation is controlled by the fer gene.37 The tomato fer mutant fails to activate iron uptake responses under Fe starvation. The fer gene was recently cloned and encodes a transcription factor with a basic Helix Loop Helix (bHLH) DNA binding domain.38 Transcription of LeNRAMP1 could well be one of the direct targets of fer action. In addition, LeNRAMP1 is up-regulated in the tomato mutant chloronerva, which behaves as constitutively iron starved plants.37,39 It will be interesting to analyze further the pathways that regulate NRAMP genes under Fe starvation. This can be done by monitoring NRAMP gene expression in known iron-response mutants or by selecting new Arabidopsis mutants defective in NRAMP induction under Fe starvation. It is also possible that some plant NRAMP genes are regulated by excess or starvation of other transition metal cations such as Zn, Mn or Cu.

Our studies using transcriptional fusions between AtNRAMP promoters and the β-glucuronidase (GUS) gene have shown that AtNRAMP3 and AtNRAMP4 are expressed in the vascular tissues of roots and shoots.47 This suggests that they could be involved in the translocation of metals between different organs of the plant. Interestingly, these studies also revealed that the up-regulation of AtNRAMP gene expression under iron starvation occurs at the transcriptional level. Indeed the GUS reporter gene under the control of either AtNRAMP3 or AtNRAMP4 promoter is activated upon Fe starvation. This is in contrast with the control of iron regulated genes in mammals, which occurs at the post-transcriptional level and involves stabilization of mRNA mediated by IRE sequences (Iron Regulatory Elements).40,41 However, AtNRAMP regulation is in agreement with the regulation of other iron responsive genes such as IRT1, IRT2 and ferritin which have been shown to be regulated at the transcriptional level in response to iron starvation.14,42,43

Finally, AtNRAMP6 cDNA with the 6th intron unspliced have been isolated in three independent laboratories (L.E. Williams personal communication, S. Thomine unpublished, http://www.rtc.riken.go.jp/). The presence of this intron introduces a premature stop codon in the protein and no functional AtNRAMP6 transporter can be translated from this cDNA. It is an attractive hypothesis that the production of AtNRAMP6 metal transporter could be regulated by differential splicing, depending on metal availability or other environmental conditions.

Analysis of NRAMP Functions in Plants

The function of metal transporters of plant NRAMP homologs has been demonstrated by expression in Saccharomyces cerevisiae, however their roles in metal homeostasis in planta have not been fully elucidated yet. The function of AtNRAMP1 and 3 has been investigated by the analysis of plants in which NRAMP genes have been disrupted or overexpressed. Curie and collaborators have constructed Arabidopsis lines that overexpress AtNRAMP1 by transforming plants with a construct containing AtNRAMP1 cDNA under the control of the strong constitutive promoter CaMV35S from the Cauliflower Mosaic Virus (35SAtNRAMP1). These plants do not display any obvious phenotype when they are grown with sufficient iron (50 μM). However, when they are grown on high toxic concentrations of iron (0.3-0.8 mM), they appear to be significantly more resistant to iron toxicity than control plants.22 The same authors have also isolated plants carrying an insertion of the T-DNA from Agrobacterium tumefaciens in the AtNRAMP1 gene. In agreement with the phenotype of the CaMV35S-AtNRAMP1 Arabidopsis, the mutant plants homozygous for the disrupted AtNRAMP1 allele are hypersensitive to toxic iron concentrations.22 Taken together, these results point to a function of AtNRAMP1 in iron homeostasis in Arabidopsis. This function is likely mediated by the iron transport function of AtNRAMP1 demonstrated by complementation of the yeast iron uptake mutant, fet3fet4. However, these results do not support a role of AtNRAMP1 for iron uptake in plant cells. In this case, AtNRAMP1 overexpression would be predicted to lead to hypersensitivity rather than resistance to toxic iron concentrations.

Computer predictions based on the proteomic analysis of the plastid envelope give a very high probability for the AtNRAMP1 protein to be located in plastids.44,45 This prediction needs to be supported by experimental determination of AtNRAMP1 subcellular localization. Together with the expression AtNRAMP1 gene in roots, its plastidial localization would raise the exciting hypothesis that plastids, which contain the iron storage protein phytoferritin,46 participate in Fe homeostasis in plant roots (Fig. 3A). It will be interesting to investigate the metal content and distribution in plants overexpressing AtNRAMP1 or carrying a T-DNA insertion in this gene.

Figure 3. Models for AtNRAMP1 and AtNRAMP3 function.

Figure 3

Models for AtNRAMP1 and AtNRAMP3 function. Predicted or experimentally determined membrane localizations of AtNRAMP proteins indicate a function in intracellular metal homeostasis.

We have used a parallel approach to analyze the function of AtNRAMP3 and AtNRAMP4 genes. Plants overexpressing AtNRAMP3 under the control of the 35SCaMV promoter did not display any obvious developmental phenotype when grown on complete plant medium. However, when they were grown on medium supplemented with cadmium, their root growth was hypersensitive to this toxic cation.23 Plants overexpressing AtNRAMP4 also displayed cadmium hypersensitivity (S. Thomine, unpublished results). In agreement with this result, an Arabidopsis mutant carrying a T-DNA insertion in AtNRAMP3 displayed a moderate but reproducible resistance to cadmium. These results show that AtNRAMP3 and AtNRAMP4 can modulate cadmium sensitivity in planta. This is in agreement with the results obtained by expressing this gene in yeast in which AtNRAMP3 increases cadmium sensitivity and cadmium content.23 These results suggest that AtNRAMP3 could be involved in cadmium uptake into plant cells or in mobilization of cadmium from a plant cell compartment where it is sequestered. However, measurement of metal content of AtNRAMP3 over-expressing or AtNRAMP3 mutant Arabidopsis did not show any detectable difference in their cadmium content when compared with control plants. Recently, we determined the subcellular localization of AtNRAMP3 by transient expression of AtNRAMP3-GFP fusion proteins. AtNRAMP3-GFP clearly localized to the vacuolar membrane.47 Our current working hypothesis is that AtNRAMP3 could modu- late cadmium sensitivity with no modification of plant cadmium content by transporting cadmium from the vacuolar compartment, where it is sequestered, to the cytosol, where it is highly toxic (Fig. 3B).

Conclusions and Perspectives for the Analysis of Plant NRAMP Functions

As their animal and yeast counterparts, plant NRAMP genes encode transition metal transporters with a broad selectivity. In the future, it will be important to determine whether they actually transport several transition metals in vivo or if physiological conditions or cofactors present in plant cells determine a narrower selectivity. Indeed, even though bacterial NRAMPs can transport Mn and Fe, their physiological function is restricted to Mn uptake.48 It is also remarkable that the different plant NRAMP transporters differ in their selectivity. For example, whereas AtNRAMP3 and 4 share 75% identity at the amino acid level, when expressed in yeast AtNRAMP4 can transport Zn but not AtNRAMP3. It will be interesting to identify the protein domains that confer transition metal selectivity. A significant objective would be for example to dissociate transport of toxic metals such as cadmium from transport of essential micronutrients metals such as Fe, Mn and Zn to engineer crop that do not accumulate toxic metals.1 Another important goal will be to determine whether the NRAMP homologous moiety of EIN2 is a functional metal transporter and to analyze its transport properties and regulation.

Our current knowledge suggests that plant NRAMP encode intracellular metal transporters with putative subcellular localization as diverse as the plastid envelope or the vacuolar membrane. In the future, it will be important to determine systematically the subcellular localization of all plant NRAMP proteins. With such localizations, plant NRAMP proteins are expected to play important functions in intracellular metal homeostasis. However, the phenotypes of plants over-expressing AtNRAMPs or carrying disrupted alleles of AtNRAMP genes are rather subtle and can only be revealed upon treatment with the toxic metal cadmium or toxic concentrations of Fe. Given the high number of metal transporter families present in Arabidopsis, it is possible that compensation achieved by transporters from other families accounts for the lack of strong phenotypes in AtNRAMP knockout plants. Another attractive hypothesis is that there is redundancy within the NRAMP family and that knocking out more than one member of the family will be necessary to uncover the important physiological functions of plant NRAMPs. This hypothesis seems even more plausible when one considers the high number of NRAMP genes in plant genomes in comparison with yeast or mammalian genomes. It will be important to construct multiple knockout plant for several NRAMP genes to determine if severe phenotypes related to imbalances in metal homeostasis are revealed under these conditions.

Compensation or redundancy can account for the lack of strong phenotypes in the NRAMP knockout mutants but they do not account for the subtle phenotypes of plant that strongly and ectopically overexpress NRAMP genes. It is important to note that the overexpression has only been checked at the mRNA level. It is possible that strong regulation of NRAMP proteins occurs at the protein level. Such regulation has been demonstrated for yeast and plant members of the ZIP family of metal transporters and also in the case of the yeast NRAMP homolog SMF1. Future studies should thus investigate the regulation of plant NRAMP protein synthesis and degradation.

Finally, a combination of structure function analyses in heterologous expression systems, molecular genetic investigation in plants, cell biological and biochemical investigation of NRAMP protein stability and localization will provide a clearer image of NRAMP functions in plants and of their relationship with other transporters and chelators involved in metal homeostasis. The plant NRAMP family raises the question of the importance of dynamic metal compartmentalization in plant cells. The fine study of their cellular functions will require the development of new tools such as fluorescent dyes to monitor independently metal concentrations in different cell compartments.


Research in the author's laboratories was supported by CNRS and Génoplante funding to S. Thomine and NIEHS grant 1P42ES10337 to J.I. Schroeder.


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