Systems genetic analysis of multivariate response to iron deficiency in mice

Yin, Lina; Unger, Erica L.; Jellen, Leslie C.; Earley, Christopher J.; Allen, Richard P.; Tomaszewicz, Ann; Fleet, James C.; Jones, Byron C.

doi:10.1152/ajpregu.00634.2011

Cited by 21 publications

(17 citation statements)

References 70 publications

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Section: Discussionmentioning

confidence: 99%

“…ID diet also produces peripheral organ (e.g., liver and spleen) iron deficiency and may also produce an anemia in some animals (Yin, et al, 2012), thus raising concerns as to the relevance of peripheral ID effects on the ID effects found in brain. Studies utilizing a broad range of BXD RI mice strains under normal and ID condition have not identified any significant relation between peripheral iron status and VMB iron status (Jellen, et al, 2012; Yin, et al, 2012). In cell culture models, where the issue of anemia or altered peripheral metabolism are not operational, changes in DAergic system with diminished iron concentrations were similar to DAergic system changes seen in ID animal (Connor, et al, 2009; Unger, et al, 2008; Wiesinger, et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

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Low brain iron effects and reversibility on striatal dopamine dynamics

Unger

Bianco

Jones

et al. 2014

Experimental Neurology

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Iron deficiency (ID) in rodents leads to decreased ventral midbrain (VMB) iron concentrations and to changes in the dopamine (DA) system that mimic many of the dopaminergic changes seen in RLS patient where low substantia nigra iron is a known pathology of the disease. The ID-rodent model, therefore, has been used to explore the effects that low VMB iron can have on striatal DA dynamics with the hopes of better understanding the nature of iron-dopamine interaction in Restless Legs Syndrome (RLS). Using a post-weaning, diet-induced, ID condition in rats, the No-Net-Flux microdialysis technique was used to examine the effect of ID on striatal DA dynamics and it reversibility with acute infusion of physiological concentrations of iron into the VMB. This study replicated prior findings by showing that the ID condition is associated with increased extracellular striatal DA, reduced striatal DA uptake, and blunted DA-2-receptor-agonist feedback enhancement of striatal DA uptake. Despite the increase in extracellular striatal DA, intracellular striatal DA, as determined in tissue homogenates, was decrease in the ID rat. The study’s key finding was that an infusion of physiological concentrations of iron into the VMB reversed the ID-induced increase in extracellular striatal DA and the ID-induced decrease in intracellular striatal DA but had no effect on the ID-induced changes in DA uptake or on the blunted DA-uptake response to quinpirole. In summary, the ID-rodent model provides highly reproducible changes in striatal DA dynamics that remarkably parallel dopaminergic changes seen in RLS patients. Some but not all of these ID-induced changes in striatal DA dynamics were reversible with physiological increases in VMB iron. The small changes in VMB iron induced by iron infusion likely represent biologically relevant changes in the non-transferrin-bound labile iron pool and may mimic circadian-dependent changes that have been found in VBM extracellular iron.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Low brain iron effects and reversibility on striatal dopamine dynamics

Unger

Bianco

Jones

et al. 2014

Experimental Neurology

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“…Genetic analysis of iron deficiency in mice has been evaluated [119]. This study revealed that polymorphisms in multiple genes cause individual variations in iron regulation, especially in response to dietary iron challenge.…”

Section: Genetic Polymorphism Of Proteins Involved In Iron Metabolismmentioning

confidence: 99%

Physiology of Iron Metabolism

Waldvogel-Abramowski

Waeber²,

Gassner³

et al. 2014

Transfus Med Hemother

208

146

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A revolution occurred during the last decade in the comprehension of the physiology as well as in the physiopathology of iron metabolism. The purpose of this review is to summarize the recent knowledge that has accumulated, allowing a better comprehension of the mechanisms implicated in iron homeostasis. Iron metabolism is very fine tuned. The free molecule is very toxic; therefore, complex regulatory mechanisms have been developed in mammalian to insure adequate intestinal absorption, transportation, utilization, and elimination. ‘Ironomics' certainly will be the future of the understanding of genes as well as of the protein-protein interactions involved in iron metabolism.

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“…It also has a primary environmental factor of reduced peripheral iron related both to severity of RLS [39], and when severe with increased RLS prevalence [42] that can be corrected by reversing the iron deficiency [40]. One approach to establishing an animal model of RLS other than disrupting known genes would be to find an inbred mouse strain whose genetics produce the biological findings of RLS when exposed to the primary environmental factor, i.e.…”

Section: 0 Forward Genetics Analysis Identifies a Mouse Strain Thatmentioning

confidence: 99%

“…The VMB iron concentrations for controls varied by about 25% over the strains while the difference between control and ID for each strain varied between 0 and 35% [41]. Moreover there was no correlation between the ID effects on VMB and hemoglobin or other peripheral measures of iron (data from a prior study [42] (see Figure 1). One mouse strain (strain 40 females) showed the biological phenotype of response to iron deficiency producing reduced VMB iron with minimal change in hemoglobin.…”

Section: 0 Forward Genetics Analysis Identifies a Mouse Strain Thatmentioning

confidence: 99%

Animal models of RLS phenotypes

Allen¹,

Donelson

Jones

et al. 2017

Sleep Medicine

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Restless legs syndrome (RLS) is a complex disorder involving sensory and motor systems. The major pathophysiology of RLS is low iron concentration in the substantia nigra, containing the cell bodies of dopamine neurons that project to the striatum, an area important for modulating movement. People who have RLS often present with normal iron values outside the brain and recent studies implicate several genes involved in the syndrome. Like most complex diseases, animal models usually do not faithfully capture the full phenotypic spectrum of “disease” which is a uniquely human construct. Nonetheless, animal models have proven useful in helping to unravel the complex pathophysiology of diseases such as RLS and suggest novel treatment paradigms. For example, hypothesis-independent genome-wide association studies (GWAS) have identified several genes as increasing risk for RLS, including BTBD9. Independently, the murine homolog, Btbd9 was identified as a candidate gene for iron regulation in the midbrain in mice. The relevance of the phenotype of another of the GWAS identified genes, MEIS1, has also been explored. The role of Btbd9 in iron regulation and RLS-like behaviors has been further evaluated in mice carrying a null mutation of the gene, and in fruit flies when the BTBD9 protein is degraded. The BTBD9 and MEIS1 stories took origin from human GWAS research, supported by work in a genetic reference population of mice (forward genetics), and further verified in mice, fish flies and worms. Finally, the role of genetics is further supported by an inbred mouse strain that displays many of the phenotypic characteristics of RLS. The role of animal models of RLS phenotypes is also extended to include periodic limb movements.

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Systems genetic analysis of multivariate response to iron deficiency in mice

Abstract: A, Fleet JC, Jones BC. Systems genetic analysis of multivariate response to iron deficiency in mice.

Cited by 21 publications

References 70 publications

Low brain iron effects and reversibility on striatal dopamine dynamics

Low brain iron effects and reversibility on striatal dopamine dynamics

Physiology of Iron Metabolism

Animal models of RLS phenotypes

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