Biomedical subjects

J R Connor

Publications and source records attributed to J R Connor.

At least 55 records · Page 3Linked to original sources

PubMed2000

Iron deficiency alters H- and L-ferritin expression in rat brain.

Ferritin (Ft) H and L subunits are independently regulated proteins with both transcriptional and translational regulation in response to cellular iron levels. While the heterogeneous distribution of ferritin and iron in the brain is now well established, the relative response of each subunit to iron deficiency and iron supplementation, is not well defined. Weanling male Sprague-Dawley rats (n=12 per group) were randomly assigned to an iron deficient (3.5 mg Fe/kg diet), control (35 mg Fe/kg diet) or supplemented (350 mg Fe/kg diet) diet for six weeks. The H-/L-ferritin subunit ratio and mRNA levels were determined. Overall, the protein ratio in control rats of H to L was approximately 45:1 compared to a ratio >60:1 in iron deficiency but the absolute amounts of each subunit varied greatly from one brain region to another. The ratio of H-:L-ferritin mRNA was 6:1 and was not affected by dietary iron deficiency in contrast to a potent effect on mRNA levels in liver. Severe iron deficiency reduced brain ferritin H protein levels significantly in all regions, whereas only ferritin L levels in striatum, substantia nigra and pons were affected by iron deficiency. Supplemental dietary iron increased both ferritin subunits, with the largest increase (50%) in the hippocampus. These data indicate that ferritin H and L subunits within the brain respond differently to iron status and suggest post transcription regulation as a key event.

Animals↗

PubMed2000

Alterations in the interaction between iron regulatory proteins and their iron responsive element in normal and Alzheimer's diseased brains.

Iron regulatory proteins (IRPs) are cytoplasmic mRNA binding proteins involved in intracellular regulation of iron homeostasis. IRPs regulate expression of ferritin and transferrin receptor at the mRNA level by interacting with a conserved RNA structure termed the iron-responsive element (IRE). This concordant regulation of transferrin receptors and ferritin is designed so a cell can obtain iron when it is needed, and sequester iron when it is in excess. However, we have reported that iron accumulates in the brain in Alzheimer's disease without a concomitant increase in ferritin. An increase in iron without proper sequestration can increase the vulnerability of cells to oxidative stress. Oxidative stress is a component of many neurological diseases including Alzheimer's. We hypothesized that alterations in the IRP/IRE interaction could be the site at which iron mismanagement occurs in the Alzheimer's brains. In this report we demonstrate that in normal human brain extracts, the IRP is detected as a double IRE/IRP complex by RNA band shift assay, but in 2 of 6 Alzheimer's brain (AD) extracts examined a single IRE/IRP complex was obtained. Furthermore, the mobility of the single IRE/IRP complex in Alzheimer's brain extracts is decreased relative to the double IRE/IRP complex. Western blot and RNA band super shift assay demonstrate that IRP1 is involved in the formation of the single IRE/IRP complex. In vitro analyses suggest that the stability of the doublet complex and single AD complex are different. The single complex from the AD brain are more stable. A more stable IRE/IRP complex in the AD brain could increase stability of the transferrin receptor mRNA and inhibit ferritin synthesis. At the cellular level, the outcome of this alteration in the molecular regulatory mechanism would be increased iron accumulation without an increase in ferritin; identical to the observation we reported in AD brains. The appearance of the single IRE/IRP complex in Alzheimer's brain extracts is associated with relatively high endogenous ribonuclease activity. We propose that elevated RNase activity is one mechanism by which the iron regulatory system becomes dysfunctional.

Alzheimer Disease↗

PubMed1999

Transferrin is required for normal distribution of 59Fe and 54Mn in mouse brain.

Hypotransferrinemia (hpx/hpx) is a genetic defect in mice resulting in <1% of normal plasma transferrin (Tf) concentrations; heterozygotes for this mutation (+/hpx) have low circulating Tf concentrations. These mice provide a unique opportunity to examine the role of Tf in Fe and Mn transport in the brain. Twenty weanling wild-type BALB/cJ mice, 15 +/hpx mice, and 12 hpx/hpx mice of both sexes were injected i.v. with either 54MnCl(2) or 59FeCl(3) either 1 h or 1 week before killing at 12 weeks of age. Total brain counts of 54Mn and 59Fe were measured, and regional brain distributions were assessed by autoradiography. Hypotransferrinemia did not affect total brain Mn uptake. However, 1 week after i.v. injection, hpx/hpx mice had less 54Mn in forebrain structures including cerebral cortex, corpus callosum, striatum, and substantia nigra. The +/hpx mice had the highest total brain 59Fe accumulation 1 h after i.v. injection. A striking effect of regional distribution of 59Fe was noted 1 week after injection; in hpx/hpx mice, 59Fe was located primarily in choroid plexus, whereas in +/+ and +/hpx mice 59Fe was widely distributed, with relatively high amounts in cerebral cortex and cerebellum. We interpret these data to mean that Tf is necessary for the transport of Fe but not Mn across the blood-brain barrier, and that there is a Tf-independent uptake mechanism for iron in the choroid plexus. Additionally, these data suggest that endogenous synthesis of Tf is necessary for Fe transport from the choroid plexus.

Animals↗

PubMed1999

Screening of transcriptionally regulated genes following iron chelation in human astrocytoma cells.

Deferoxamine is an effective iron chelator and a potential therapeutic agent for use in minimizing free radical-mediated injury following trauma. Iron chelation may also be an effective means of limiting tumor growth by decreasing bioavailable iron. Deferoxamine can modulate gene expression through manipulation of intracellular iron levels; specifically at the posttranscription level by changing the activity of iron regulatory proteins (IRPs). The effect of iron chelation on the transcription of genes is still unclear, but iron-binding sites on DNA have been reported. Here we investigate the influence of deferoxamine on gene transcription. Two-directional (forward and backward) suppression subtraction hybridization (SSH) was performed on human astrocytoma cells (SW1088) cultured in either standard media or treated for 48 hours with deferoxamine. To restrict the number of false-positive clones, reverse Northern blotting was used to further verify the differentially expressed cDNA clones. Positive clones were sequenced and the mRNAs were re-examined on Northern blots for changes in expression over time of deferoxamine exposure. The results of these analyses have identified both novel and known genes whose expression is influenced by iron chelation. The known genes include a group related to energy production and a group related to protease function. These results provide examples of genes not previously known to be directly influenced by iron availability, and as such may be potential targets for iron chelation therapy.

Astrocytoma↗

PubMed1999

Identification and cloning of a connective tissue growth factor-like cDNA from human osteoblasts encoding a novel regulator of osteoblast functions.

We have identified and cloned a novel connective tissue growth factor-like (CTGF-L) cDNA from primary human osteoblast cells encoding a 250-amino acid single chain polypeptide. Murine CTGF-L cDNA, encoding a polypeptide of 251 amino acids, was obtained from a murine lung cDNA library. CTGF-L protein bears significant identity ( approximately 60%) to the CCN (CTGF, Cef10/Cyr61, Nov) family of proteins. CTGF-L is composed of three distinct domains, an insulin-like growth factor binding domain, a von Willebrand Factor type C motif, and a thrombospondin type I repeat. However, unlike CTGF, CTGF-L lacks the C-terminal domain implicated in dimerization and heparin binding. CTGF-L mRNA ( approximately 1.3 kilobases) is expressed in primary human osteoblasts, fibroblasts, ovary, testes, and heart, and a approximately 26-kDa protein is secreted from primary human osteoblasts and fibroblasts. In situ hybridization indicates high expression in osteoblasts forming bone, discrete alkaline phosphatase positive bone marrow cells, and chondrocytes. Specific binding of 125I-labeled insulin-like growth factors to CTGF-L was demonstrated by ligand Western blotting and cross-linking experiments. Recombinant human CTGF-L promotes the adhesion of osteoblast cells and inhibits the binding of fibrinogen to integrin receptors. In addition, recombinant human CTGF-L inhibits osteocalcin production in rat osteoblast-like Ros 17/2.8 cells. Taken together, these results suggest that CTGF-L may play an important role in modulating bone turnover.

Amino Acid Sequence↗

PubMed1999

Distribution of transferrin and ferritin binding in normal and multiple sclerotic human brains.

Delivery of iron to the brain traditionally has been considered the responsibility of transferrin. However, transferrin receptors in brain are located primarily within gray matter areas rather than in the iron rich white matter tracts. In this report we present the first demonstration of ferritin binding sites in human brain and provide evidence that these binding sites are primarily in white matter tracts. This distribution of ferritin binding is opposite of that seen for the distribution of the transferrin receptor in normal adult human brain. Ferritin binds to human brain tissue in a competitive and saturable manner with a dissociation constant of 0.35 nM and a binding site density of 116.7 fmol/mg protein. In brain tissue from multiple sclerotic (MS) patients the normal pattern of transferrin and ferritin binding distributions is disrupted. Ferritin binding is absent in the lesion itself and in the immediate periplaque region within the white matter but returns to normal as the distance from the lesion becomes greater. In direct contrast to ferritin binding, transferrin binding in the MS tissue is present in the white matter tracts, but only in the periplaque region. The periplaque region also contains transferrin receptor positive cells (as determined by immunocytochemistry) morphologically consistent with oligodendrocytes. Gray matter binding of transferrin in MS patients appears normal. These data provide the initial evidence of ferritin binding in human brain, address the enigma of the apparent absence of an iron delivery system to the iron-rich white matter, and suggest loss of ferritin binding is involved in or is a consequence of demyelination associated with MS.

Adult↗

PubMed1999

Existing and emerging mechanisms for transport of iron and manganese to the brain.

The metals iron (Fe) and manganese (Mn) are essential for normal functioning of the brain. This review focuses on recent developments in the literature pertaining to Fe and Mn transport. These metals are treated together because they appear to share several transport mechanisms. In addition, several neurological diseases such as Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease are all associated with Fe mismanagement in the brain, particularly in the striatum and basal ganglia. Similarly, Mn accumulation in brain also appears to target the same brain regions. Therefore, stringent regulation of the concentration of these metals in the brain is essential. The homeostatic mechanisms for these metals must be understood in order to design neurotoxicity prevention strategies.

Animals↗

PubMed1999

Influence of nitric oxide on cellular and mitochondrial integrity in oxidatively stressed astrocytes.

Astrocytes provide protection and trophic support to neurons, but like neurons are vulnerable to oxidative stress. Decreased function of astrocytes resulting from oxidative stress could contribute to neurodegeneration. Our goal is to understand the intracellular events associated with oxidative stress in astrocytes. Because nitric oxide (NO) has been implicated as a contributor to oxidative stress in the brain, we examined in this study whether NO contributed to oxidative stress in astrocytes. Stimulation of NO decreases superoxide levels, preserves mitochondrial membrane potential, and decreases mitochondrial swelling in astrocytes treated with peroxide. Chelation of NO is associated with increased cell death, mitochondrial swelling, and loss of mitochondrial membrane potential, in response to peroxide treatment. Peroxide treatment increased intracellular calcium and the peroxide-induced changes in intracellular calcium were not altered in response to NO. Iron-loading increases peroxide-induced oxidative stress in astrocytes, but induction of NO limited the iron effect, suggesting an interaction between iron and NO. These data suggest endogenously produced NO protects astrocytes from oxidative stress, perhaps by preserving mitochondrial function.

Animals↗

PubMed1999

Changes in iron histochemistry after hypoxic-ischemic brain injury in the neonatal rat.

Iron can contribute to hypoxic-ischemic brain damage by catalyzing the formation of free radicals. The immature brain has high iron levels and limited antioxidant defenses. The objective of this study was to describe the early alterations in nonheme iron histochemistry following a hypoxic-ischemic (HI) insult to the brain of neonatal rats. We induced a HI insult to the right cerebral hemisphere in groups of 7-day-old rats. Rats were anesthetized, then their brains were perfused and fixed at 0, 1, 4, 8, 24 hr, and 1, 2, and 3 weeks of recovery. Forty-micron-thick frozen sections were stained for iron using the intensified Perls stain. Increased iron staining was first detected within the cytoplasm of cells with pyknotic nuclei at 4 hr of recovery. Staining increased rapidly over the first 24 hr in regions of ischemic injury. By 7 days recovery, reactive glia and cortical blood vessels also stained. Increased staining in gray matter persisted at 3 weeks of recovery, whereas white matter tracts had fewer iron-positive cells compared to normal. The early increase in iron staining could be caused by an accumulation of iron posthypoxicischemic injury or a change in iron from nonstainable heme iron to stainable nonheme iron. Regardless of the source, our results indicate that there is an increase in iron available to promote oxidant stress in the neonatal rat brain following hypoxia-ischemia.

Animals↗

PubMed1999

Influence of calcium and iron on cell death and mitochondrial function in oxidatively stressed astrocytes.

Astrocytes protect neurons and oligodendrocytes by buffering ions, neurotransmitters, and providing metabolic support. However, astrocytes are also vulnerable to oxidative stress, which may affect their protective and supportive functions. This paper examines the influence of calcium and iron on astrocytes and determines if cell death could be mediated by mitochondrial dysfunction. We provide evidence that the events associated with peroxide-induced death of astrocytes involves generation of superoxide at the site of mitochondria, loss of mitochondrial membrane potential, and depletion of ATP. These events are iron-mediated, with iron loading exacerbating and iron chelation reducing oxidative stress. Iron chelation maintained the mitochondrial membrane potential, prevented peroxide-induced elevations in superoxide levels, and preserved ATP levels. Although increased intracellular calcium occurred after oxidative stress to astrocytes, the calcium increase was not necessary for collapse of mitochondrial membrane potential. Indeed, when astrocytes were oxidatively stressed in the absence of extracellular calcium, cell death was enhanced, mitochondrial membrane potential collapsed at an earlier time point, and superoxide levels increased. Additionally, our data do not support opening of the mitochondrial permeability transition pore as part of the mechanism of peroxide-induced oxidative stress of astrocytes. We conclude that the increase in intracellular calcium following peroxide exposure does not mediate astrocytic death and may even provide a protective function. Finally, the vulnerability of astrocytes and their mitochondria to oxidative stress correlates more closely with iron availability than with increased intracellular calcium.

Adenosine Triphosphate↗

PubMed1999

Rat model of perinatal hypoxic-ischemic brain damage.

To gain insights into the pathogenesis and management of perinatal hypoxic-ischemic brain damage, the authors have used an immature rat model which they developed many years ago. The model entails ligation of one common carotid artery followed thereafter by systemic hypoxia. The insult produces permanent hypoxic-ischemic brain damage limited to the cerebral hemisphere ipsilateral to the carotid artery occlusion. The mini-review describes recently accomplished research pertaining to the use of the immature rat model, specifically, investigations involving energy metabolism, glucose transporter proteins, free radical injury, and seizures superimposed upon cerebral hypoxia-ischemia. Future research will focus on molecular mechanisms of neuronal injury with a continuing focus on therapeutic strategies to prevent or minimize hypoxic-ischemic brain damage.

Animals↗

PubMed1999

Expression of cathepsin K messenger RNA in giant cells and their precursors in human osteoarthritic synovial tissues.

OBJECTIVE: To investigate the expression of cathepsin K messenger RNA (mRNA) in the giant cells found in human osteoarthritic (OA) synovium and associated reparative connective tissues, and to compare this with mRNA expression of cathepsins B, L, and S, which are cysteine proteases known to be highly expressed by cells of the monocyte/macrophage lineage. METHODS: Sections of human OA synovium were processed for in situ hybridization and probed for cathepsins K, B, L, and S. Serial sections were reacted for tartrate-resistant acid phosphatase (TRAP) and nonspecific esterase (NSE) activity, which are selective markers for the osteoclast and cells of the macrophage/monocyte lineage, respectively. RESULTS: At 3 sites of monocyte infiltration/giant cell formation (granulation tissue, the intimal and subintimal synovial layers, and deep stroma extending to the periphery of osteophytic tissue), both TRAP-positive mono- and multinucleated cells and TRAP-negative, NSE-positive mononuclear precursors were identified. Cells containing both enzyme activities were also found, potentially indicating an intermediate stage of differentiation. The TRAP-positive mononuclear/giant cells, and the occasional NSE-positive precursor, expressed an intense signal for cathepsin K mRNA, but did not express cathepsins B, L, and S. In contrast, the deep zone of phagocytic-like cells adjacent to sites of ossification expressed high levels of mRNA for cathepsins L, B, and S as well as cathepsin K mRNA. CONCLUSION: Giant cells that form within OA synovial tissue express high levels of cathepsin K mRNA. It appears that cathepsin K acts principally to digest the bone (and cartilage) fragments sheered from the joint surface during OA. The high TRAP activity and the undetectable expression of the macrophage-associated degradative proteases (cathepsins B, L, and S) by synovial giant cells strengthens the hypothesis that cathepsin K is the primary protease involved in bone degradation. At sites of synovial osteogenesis, a population of phagocytic-like cells expressed TRAP and cathepsins B, L, S, and K, and may represent blood-derived macrophages pushed toward an osteoclast phenotype.

Cathepsin B↗

PubMed1999

Cellular distribution of iron in the brain of the Belgrade rat.

In this study, we investigated the cellular distribution of iron in the brain of Belgrade rats. These rats have a mutation in Divalent Metal Transporter 1, which has been implicated in iron transport from endosomes. The Belgrade rats have iron-positive pyramidal neurons, but these are fewer in number and less intensely stained than in controls. In the white matter, iron is normally present in patches of intensely iron-stained oligodendrocytes and myelin, but there is dramatically less iron staining in the Belgrade rat. Those oligodendrocytes that stained for iron did so strongly and were associated with blood vessels. Astrocytic iron staining was seen in the cerebral cortex for both normal rats and Belgrade rats, but the iron-stained astrocytes were less numerous in the mutants. Iron staining in tanycytes, modified astrocytes coursing from the third ventricle to the hypothalamus, was not affected in the Belgrade rat, but was affected by diet. The results of this study indicate that Divalent Metal Transporter 1 is important to iron transport in the brain. Iron is essential in the brain for basic metabolic processes such as heme formation, neurotransmitter production and ATP synthesis. Excess brain iron is associated with a number of common neurodegenerative diseases. Consequently, elucidating the mechanisms of brain iron delivery is critical for understanding the role of iron in pathological conditions.

Amino Acid Substitution↗

PubMed1999

Characterization and distribution of ferritin binding sites in the adult mouse brain.

Studies on iron uptake into the brain have traditionally focused on transport by transferrin. However, transferrin receptors are not found in all brain regions and are especially low in white matter tracts where high iron concentrations have been reported. Several lines of research suggest that a receptor for ferritin, the intracellular storage protein for iron, may exist. We present, herein, evidence for ferritin binding sites in the brains of adult mice. Autoradiographic studies using 125I-recombinant human ferritin demonstrate that ferritin binding sites in brain are predominantly in white matter. Saturation binding analyses revealed a single class of binding sites with a dissociation constant (K(D)) of 4.65 x 10(-9) M and a binding site density (Bmax of 17.9 fmol bound/microg of protein. Binding of radiolabeled ferritin can be competitively displaced by an excess of ferritin but not transferrin. Ferritin has previously been shown to affect cellular proliferation, protect cells from oxidative damage, and deliver iron. The significance of a cellular ferritin receptor is that ferritin is capable of delivering 2,000 times more iron per mole of protein than transferrin. The distribution of ferritin binding sites in brain vis-à-vis transferrin receptor distribution suggests distinct methods for iron delivery between gray and white matter.

Age Factors↗

PubMed1999

Reduction in the structural changes of experimental osteoarthritis by a nitric oxide inhibitor.

OBJECTIVE: To evaluate the in-vivo therapeutic efficacy of N -iminoethyl-L-Lysine (L-NIL), a selective inhibitor of inducible nitric oxide synthase (iNOS) in a dose response study, on the progression of lesions in the experimental osteoarthritic (OA) dog model. DESIGN: The sectioning of the anterior cruciate ligament of the right stifle joint of mongrel dogs was done by a stab wound. Dogs were separated into experimental groups: Group 1 received no treatment, Groups 2, 3, and 4 received oral L-NIL (0.3, 1 or 10mg/kg/day, respectively) starting immediately after surgery. The OA dogs were killed at 12 weeks after surgery. RESULTS: Macroscopically, L-NIL decreased the size of the cartilage lesions on condyles and plateaus. The histologic severity of the cartilage lesions was decreased in the L-NIL-treated dogs. This effect was more pronounced at the highest dosage tested (3 and 10mg/kg/day). CONCLUSIONS: This study confirms the effectiveness of L-NIL, a selective inhibitor of iNOS, in attenuating the progression of experimental OA. It also clearly shows that the effect is dose-dependent.

Animals↗

PubMed1999

Receptor for interleukin 13 is a marker and therapeutic target for human high-grade gliomas.

Glioblastoma multiforme (GBM) is an incurable brain tumor. Due to the striking heterogeneity that characterizes GBM, there is no known tumor-specific antigen or receptor that is expressed by a majority of GBM patients. We found that virtually all studied human GBM specimens (23 samples) abundantly expressed a receptor for interleukin (IL)-13 in situ, whereas normal human brain had few, if any, IL-13-binding sites. The GBM-associated IL-13 receptor was both quantitatively and qualitatively different from and, thus, more restrictive than the shared signaling receptor of normal tissue: it was IL-4 independent. The receptor for IL-13 was overexpressed by a majority of cancer cells in situ. Furthermore, cytotoxins targeted to this more restrictive IL-13R produced cures in animals bearing xenografts of human high-grade gliomas. Thus, unexpectedly, the receptor for an immune regulatory cytokine may be a long sought marker and, concomitantly, a unique imaging site and therapeutic target for GBM, the most malignant and the most heterogeneous of brain tumors.

Adolescent↗

PubMed1999

Selective inhibition of inducible nitric oxide synthase in experimental osteoarthritis is associated with reduction in tissue levels of catabolic factors.

OBJECTIVE: We used the experimental dog model of osteoarthritis (OA) to examine the in vivo effects of N-iminoethyl-L-lysine (L-NIL), a selective inhibitor of the inducible nitric oxide synthase (iNOS), on the tissue level and distribution of interleukin-1beta (IL-1beta), collagenase-1, stromelysin-1, cyclooxygenase-2 (COX-2), iNOS and nitrotyrosine, through immunohistochemical and morphometric analysis. METHODS: Cartilage and synovial membrane specimens were obtained from 3 experimental groups of dogs: Group I--unoperated dogs that received no treatment; Group II--dogs subjected to a sectioning of the anterior cruciate ligament of the right knee and given no treatment; and Group III--operated dogs that received oral treatment with L-NIL (10 mg/kg twice daily/po) for 10 weeks starting immediately after surgery. The operated dogs were killed 10 weeks post-surgery. The tissue distributions of IL-1beta, metalloproteases (MMP), COX-2, iNOS and nitrotyrosine were documented by immunohistochemistry using specific antibodies, and quantified by morphometric analysis. RESULTS: In cartilage, the cell scores (percentage of chondrocytes staining positive for the antigen) for iNOS and 3-nitrotyrosine were dramatically enhanced in OA specimens compared to normal (p < 0.0001). However, the cartilage of dogs treated with L-NIL showed significantly lower cell scores for iNOS (p<0.0001, condyle; p<0.001, plateau), nitrotyrosine (p<0.0004; p<0.0001) and COX-2 (p<0.0001; p<0.001) compared to that of untreated OA dogs. Similar findings were observed for collagenase-1 and stromelysin-1, where the increased cell scores of these 2 MMP in OA cartilage were reduced after treatment with L-NIL (collagenase: p<0.002, condyle; p<0.0003, plateau; stromelysin: p<0.006; p<0.0001). The increased cell scores for the IL-1beta, COX-2, iNOS and nitrotyrosine found in the synovial lining and mononuclear cell infiltrate of operated animals were also found to be markedly reduced in dogs treated with L-NIL. CONCLUSION: Our study demonstrates for the first time in vivo in an experimental model of OA, that a selective inhibition of iNOS by L-NIL and the subsequent decreased production of NO also results in a marked decrease in production of major catabolic factors such as MMP, IL-1beta and peroxynitrite, as well as a reduction in COX-2 expression.

Animals↗

PubMed1998

Cellular distribution of ferritin subunits in postnatal rat brain.

The normal development of the brain requires finely coordinated events, many of which require iron. Consequently, iron must be available to the brain in a timely manner and in a bioavailable form. However, the brain also requires stringent mechanisms to protect itself from iron-induced oxidative damage. The protein that is best suited to making iron available but also adequately protecting the cell is the intracellular iron storage protein ferritin. Typically, ferritin is composed of 24 subunits of H and L chains, which are functionally distinct. This study was undertaken to determine the expression of ferritin subunits during normal development of the postnatal rat brain. There is a shift in ferritin-containing cell types during development from predominantly microglia at postnatal day 5 (PND 5) to predominantly oligodendrocytes by PND 30. At PND 5, microglia are found throughout gray and white matter areas of the brain, but only amoeboid microglia in discrete foci in the subcortical white matter are ferritin positive. At PND 15, some oligodendrocytes in the subcortical white matter express ferritin, but the majority of ferritin-containing cells within white matter are still microglia. By PND 30, the predominant ferritin-containing cell type within white matter are oligodendrocytes. Generally, the cellular distribution of both ferritin subunits were identical with one major exception; H-ferritin, but not L-ferritin, was present in neuronal nuclei in the cortex. These data suggest that microglia play a role in brain iron homeostasis during normal postnatal development and may influence myelination by competing with oligodendrocytes for iron.

Animals↗