KEY WORDS  Transferrin,
Ferritin, Brain, Metals,
            Neuroglia, Oxidative stress, Cytokines

ABSTRACT Oligodendrocytes are the predominant iron-containing cells in the brain. Iron-containing oligodendrocytes are found near neuronal cell bodies, along blood vessels, and are particularly abundant within white matter tracts. Iron-positive cells in white matter are present from birth and eventually reside in defined patches of cells in the adult. These patches of iron-containing cells typically have a blood vessel at their center. Ferritin, the iron storage protein, is also expressed early in development in oligodendrocytes in a regional and cellular pattern similar to that seen for iron. Recently, the functionally distinct subunits of ferritin have been analyzed; only (H)-chain ferritin is found in oligodendrocytes early in development. H-ferritin is associated with high iron utilization and low iron storage. Consistent with the expression of H-ferritin is the expression of transferrin receptors (for iron acquisition) on immature oligodendrocytes. Transferrin protein accumulation and mRNA expression in the brain are both dependent on a viable population of oligodendrocytes and may have an autocrine function to assist oligodendrocytes in iron acquisition. Although apparently the majority of oligodendrocytes in white matter tracts contain ferritin, transferrin, and iron, not all of them do., indicating that there is a subset of oligodendrocytes in white matter tracts. The only known function of oligodendrocytes is myelin production and both a direct and indirect relationship exists between iron acquisition and myelin production. Iron is directly involved in myelin production as a required co-factor for cholesterol and lipid biosynthesis and indirectly because of its requirement for oxidative metabolism (which occurs in oligodendrocytes at a higher rate than in other brain cells). Factors (such as cytokines) and conditions such as iron deficiency may reduce iron acquisition by oligodendrocytes and the susceptibility of oligodendrocytes to oxidative injury may be a result of their iron-rich cytoplasm. Thus, the many phenomena that decrease oligodendrocyte survival and/or myelin production may mediate their effect through a final common pathway that involves disruptions in iron availability or intracellular management of iron. © 1996 Wiley-Liss, Inc.

Iron is abundant in the brain; the basal ganglia alone have iron levels equal to those in the liver on a per weight basis (Hallgren and Sourander, 1958). The abundance of iron in the brain is not surprising. Iron is a basic requirement for oxidative metabolism and the brain has a higher rate of oxidative metabolism than any other organ (Ikeda and Long, 1990). If iron availability is insufficient, irreversable cognitive and motor impairment can occur (Walter, 1990). However, iron accumulation must be regulated since iron excess can be pathogenic through its potent ability to induce free radicals and hence oxidative damage. Indeed, the abundance of iron has stimulated considerable examination into the possibility that this metal is the major culprit in initiation of oxidative damage in biological systems (Halliwell et al., 1992; Ikeda and Long, 1990). Abnormal accumulation of iron and oxidative injury has been demonstrated in a number of neurological disorders including multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and Hallervorden-Spatz Syndrome. (Drayer et al., 1987; Olanow, 1993; Swaiman, 1991).

The regulation and management of iron at the cellular level is primarily by four proteins found in most cell throughout the body: transferrin (Tf), transferrin receptor, ferritin and the iron regulatory protein (IRP) (Fig. 1). When cells are in need of iron, Tf receptors are added to the cell surface, where they bind with Tf. Tf carries two iron atoms, and the Tf-iron complex is internalized. Iron is removed from Tf in endolysosomal compartments and transported from lysosomes in a manner not understood. Tf (minus the iron) is recycled to the cell surface still attached to its receptor and dissociates from receptor at the cell surface. Once inside the cell, if not immediately required in the myriad of metabolic processes in which it plays a role, iron is stored in ferritin (Aisen, 1992). Ferritin, the intracellular iron storage protein, is a dynamic protein made of differing ratios of two subunits and will be discussed in more detail below. Another protein identified as responsible for maintenance of cellular iron homeostasis by coordinating ferritin and Tf receptor translation in response to iron availability in the cell is the IRP. There is very little information about the IRP in brain, and it will not be discussed in this review.

The brain contains each of the identified iron management proteins mentioned in the preceding paragraph, but it provides a unique challenge to management of iron availability at both the organ and cellular levels. The brain resides behind a barrier and thus does not have immediate access to plasma iron. In addition, the brain is compartmentalized according to function, and hence metabolic requirements within this organ change with activity. Subsequently, iron requirements are not consistent among the different parts of the brain, a finding exemplified in the large variation in amounts of iron per brain region (Focht et al., submitted; Hallgren and Sourander, 1958; hill and Switzer, 1984). The focus of this review is on the cellular distribution of iron and the iron management proteins in oligodendrocytes. A recent review of the biochemical studies from our laboratory has been published (Connor, 1994) as well as an overview of iron requirements for brain activity (Beard et al., 1993).

IRON

It is now established in a number of species that the principle cells in the brain (regardless of brain region) that stain following iron histochemistry are oligodendrocytes. (Benkovic and Connor, 1993; Connor et al., 1990; Dwork et al., 1988; Hill and Switzer, 1984; Levine and Macklin 1990; Morris et al., 1992). Iron-containing cells are found in perineuronal satellite positions in all gray matter ares of the brain and spinal cord. Iron-positive cells are abundant in whie matter tracts consistent with reports that iron levels in white matter are higher than in gray matter (Connor, 1992; Curnes et al., 1988 Rajan et al., 1976). Within white matter, iron-positive cells occur in patches and appear to have a blood vessel in the center of each patch of cells. The association of iron-positive cells in white matter with blood vessels is most obvious in rat and mouse brains (Connor and Menzies, 1990; Dickinson and Connor, 1995. Iron cells in patches in white matter (Fig. 2) are seen in mouse, rat, monkey and human (Connor and Menzies 1990; Connor et al., 1990; Dickinson and Connor, 1995; Dwork et al., 1988). Iron reaction product is not confined to the cell soma within the patch of iron-stained cells. The area surrounding the cells within the patch also stains for iron (Connor and Menzies, 1995) and may be associated with oligodendrocytic cytoplasm surrounding the axons (Francois et al., 1981).

In the neonate, iron-positive cells in white matter tracts are almost exclusively found in areas reported to be myelogenic foci (Connor, 1994). If oligodendrocytes are present but fail to mature (myelin deficient rats), brain iron uptake is normal (Gocht et al., 1993), but the iron accumulates in astrocytes and microglia in white matter tracts (Connor and Menzies, 1990). If oligodendrocytes reach mature stages and produce myelin, even if the myelin is abnormal (shiverer mice, quaking mice) iron accumulation in oligodendrocytes (Connor et al., 1993; Levine, 1991) Thus, iron accumulation by oligodendrocytes may be a requirement for onset of myelination. Consistent with this concept are the observations that: 1) peak iron uptake in the brain coincides with the onset of myelination (Crowe and Morgan, 1992); 2) iron is required for galactocerebroside expression by oligodendrocytes in culture (Eccleston and Silberberg, 1984); and 3) iron deficiency is associated with hypomyelination (Larkin and Rao, 1990), possibly through specific reduction in myelin lipids (Oloyede et al., 1992). We have also shown that prenatal ethanol exposure can alter the iron acquisition pattern during postnatal development (Miller et al., 1994) and prenatal ethanol exposure is also assiciated with delayed onset of myelination (see references to Miller et al., 1994) suggesting that a possible common denominator for hypomyelination may be insufficient iron delivery to oligodendrocytes.

Iron is required for cholesterol and lipid synthesis, both of which are abundant in and key components of myelin (Larkin and Rao, 1990). Furthermore, cholesterol and lipid synthesis occurs at a higher rate in oligodendrocytes than any other cell type in the brain (Cammer, 1984; Pleasure et al.,1984). Indeed, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase , the initial step in cholestyerol biosynthesis is considered a marker for oligodendrocytes (Pleasure et al., 1977). Iron-requiring enzymes leading to lipid synthesis (fatty acid desaturase) and degradation (lipid dehydrogenases) are enriched in oligodendrocytes (Bourre et al., 1984; Cammer, 1984; Tansey and Cammer., 1988). The peripheral demyelination associated with tellurium toxicity is thought to result from blockage of the iron-requiring squalene oxidase step in cholesterol biosynthesis. (Wagner-Recio et al., 1991).

Iron is also involved in myelin production through its essential role in oxidative metabolism. Oligodendrocytes reported have the highest rate of oxidative metabolic activity of any cell in the brain on a per volume basis, with cell respiration rates at least 2X that of neurons (Cammer, 1984; Hyden and Pigon, 1960). Specific iron-requiring enzymes involved in maintaining a high rate of metabolic activity such as glucose-6-phosphate dehydrogenase, deoxygenase, succinic dehydrogenase, and NADH dehydrogenase, as well as the cytochrome oxidase system, are all elevated in oligodendrocytes relative to other cells in the brain (Cammer, 1984). Oligodendrocytes reportedly use the pentose phosphate pathway for glucose metabolism (Cammer, 1984). During peak myelination, 60% of the glucose utilized by the brain is metabolized via the pentose phosphate pathway. After maximal rates of myelination have passed, the amount of glucose utilized in brain via the pentose phosphate pathway drops, but is still at 25%. Thus it follows that iron would be most concentrated in the cells with the highest level of oxidative metabolism, especially given the relatively low volume of cytoplasm in oligodendrocytes. The high rate of oxidative metabolism is presumably associated with the enormous stress on the oligodendrocytes to maintain a membrane (myelin sheath), which can be 100X the weight of the cell (Morel and Toews, 1984). This high respiration rate and iron requirement is probably why oligodendrocytes are so highly vulnerable to conditions of metabolic stress such as cyanide toxicity and postnatal starvation (Wiggins et al., 1976). Clearly, the energy expenditure and hence iron requirement by oligodendrocytes for synthesis and maintenance of myelin is very high.

It could be predicted that given the high intracellular iron concentrations, the high rate of oxidative metabolism, and the rich lipid environment of oligodendrocytes, that these cells would be vulnerable to oxidative damage. Recent evidence clearly indicates that oligodendrocytes do have heightened vulnerability to oxidative stress and injury (Griot et al., 1990; Kim and Kim, 1991; Oka et al., 1993) In further support of the high rate of oxygen consumption and susceptibility to oxygen by-products in oligodendrocytes is the abundance of catalase-rich peroxysomes in oligodendrocytes (kim and Kim, 1991; Noble et al., 1994). The function of catalase (another heme-containing enzyme elevated in oligodendrocytes) is to detoxify H₂O₂, a normal by-product of oxygen metabolism.

The mounting evidence that iron-laden oligodendrocytes are vulnerable to oxidative stress suggests that emphasis should be given to analyzing a possible relationship between oxidative stress and demyelinating disorders. In support of this idea are two studies showing that demyelination and behavioral abnormalities associated with experimental allergic encephalomyelitis are suppressed when inoculated animals are treated with antioxidants (Hartung et al., 1988) or an iron chelator (Bowern et al., 1984). Circumstantial evidence that oxidative stress could be related to demyelination is provided by observations that macrophages from patients with multiple sclerosis have increased production of superoxide radicals and hydrogen peroxide (Fisher et al., 1988). The release of superoxide radicals from macrophages is part of the microbicidal and tumoricidal activity of these cells (Takemura and Werb, 1984) but may exacerbate myelin breakdown in the multiple sclerosis lesion site (Fisher et al., 1988; Johnson et al., 1989). A role for free radical-induced lipid damage and subsequent demyelination may extend beyond multiple sclerosis, since siderotic microglia have been reported in white matter of patients with acquired immunodeficiency syndrome (Gelman et al., 1992).

If the oligodendrocyte population fails to thrive, then both Tf (Connor et al., 1987) and Tf mRNA (Batrlett et al., 1991) expression in brain are drastically decreased relative to normal. When the oligodendrocytes thrive, even in the absence of myelin production, the Tf and Tf mRNA levels in brain are normal (Connor et al., 1993) From these studies it is clear that Tf expression in brain is connected to the viability of oligodendrocytes but not the quality of the myelin produced.

The role of Tf in the maturation of oligodendrocytes and production of myelin has been addressed in in vitro studies, but the results are controversial. Contradictory reports exist that Tf is essential for oligodendrocyte survival (Bottenstein, 1986; Ecclestein and Silberberg, 1984; Saneto and DeVellis, 1985) and that oligodendrocytes (Espinosa de los Monteros et al., 1990), a (the) confounding variable in these experiments may be the amount of Tf produced by oligodendrocytes in the different culture conditions. We are addressing the controversial issue of Tf and oligodendrocyte maturation by studying a spontaneously occurring mutant that has a splicing defect in the Tf gene (Huggenvik et al., 1989). The resulting phenotype has <1% of the normal plasma circulating levels of Tf (Bernstein, 1987). The <1% circulating levels of Tf are not sufficient to maintain a viable animal, so the affected mice must be injected with Tf from birth. Even with aggressive replacement of Tf, the adult transferrinemic (Hp) mouse is hypomyelinated (Dickinson and Connor, 1994). Our studies on the Hp mouse have shown that the iron staining pattern in this animal is normal (Dickinson and Connor, 1995). We have further demonstrated that the injected Tf enters the brain, finds its way to oligodendrocytes, and presumably has delivered the iron found in the oligodendrocytes (Dickinson and Connor, 1995). The studies on the Hp mouse reveal that oligodendrocytes can survive without making Tf, but the hypomyelination indicates the importance of endogenously produced brain Tf for myelin production. The endogenously produced Tf may help oligodendrocytes acquire iron or may mobilize the iron intracellularly. Brain Tf levels increase when systemic iron levels are decreased through iron-deficient diets (Chen et al., 1995). If the source of this increased brain Tf is from oligodendrocytes, this would support our idea that Tf is synthesized (secreted?) by oligodendrocytes to assist the brain in obtaining iron. Additional studies with the Hp mouse that will address this issue are in progress.

Developmentally, Tf protein levels are highest in the brain at birth and then decline over the first 2 postnatal weeks (Connor), 1994). The decline in brain Tf protein levels is coupled with an increase in the expression of Tf mRNA in the brain (Bartlett et al., 1991; Levine et al., 1984). The postnatal increase in Tf mRNA levels and the decline in Tf protein concentration are associated with closure of the blood-brain barrier and the appearance of Tf-containing oligodendrocytes in the brain, initially in the white matter (Connor and Fine, 1987). The cellular immunolabeling pattern for Tf in white matter is more evenly distributed than that seen for iron. In striking contrast to iron, Tf-positive cells are not found in myelinogenic foci nor are they particularly distributed along blood vessels. This lack of overlap between iron (and ferritin) and Tf in white matter is discussed later.

The expression of Tf mRNA in the adult brain is in oligodendrocytes (Bloch et al., 1985). Developmentally, Tf mRNA has a homogenous distribution in gray and white matter at postnatal day 7, but by postnatal day 14, Tf mRNA is predominantly in white matter (Fig. 3). This latter observation is consistent with the requirement of a thriving population of oligodendrocytes for Tf mRNA expression in brain.

The bulk of the Tf receptors expressed in the adult brain are on the microvasculature (Jeffries et al., 1984); Kalara et al., 1992) and neurons with light labeling of the oligodendrocytes (Connor and Menzies, 1995; Giometto et al., 1990). Autoradiographic studies on adult rats report that levels of Tf receptors are higher in gray matter than in white matter (Hill et al., 1985; Mash et al., 1990). The relatively low level of Tf receptors on oligodendrocytes may reflect a negative feedback relationship between iron accumulation and Tf receptor expression. However, because the iron-containing oligodendrocytes have such a precise distribution in white matter, it could be expected that the iron-rich oligodendrocytes in white matter (not in the patches of iron-positive cells) would label more intensely with antiserum to the Tf receptor, but that has not been our experience. To our knowledge, in situ hybridization studies localizing the Tf receptor mRNA in brain have not been performed.

Tf receptors are expressed by oligodendrocytes during their initial stages of development both in vivo (Lin and Connor, 1989) and in vitro (unpublished data). Both in vivo (optic nerve) and in vitro, the appearance of Tf receptor-positive cells precedes the expression of Tf, myelin basic protein, and galactocerebroside. The expression of Tf receptors by oligodendrocytes decreases in density with age (lin and Connor, 1989) in association with increased cellular iron accumulation. Kaur and Lin (1995) did not observe Tf receptor-positive oligodendrocytes in the first 10 postnatal days in rats, but did see Tf receptor-positive cells, which they characterize as microglia. Curiously, no Tf receptor cellular immunostaining was seen in their study after postnatal day 10, a time when iron uptake into brain is beginning to peak (Crowe and Morgan, 1992) and the distribution of iron-positive cells has not reached the mature pattern (Connor et al., 1995b). In a Tf receptor binding analysis on myelin-deficient rats (17-20 days old), which have no mature oligodendrocytes, a 50% loss of Tf receptors was noted (roskams and Connor, 1992). These biochemical studies suggest that total Tf receptor expression in brain receives a significant contribution from oligodendrocytes. Clearly further analysis of Tf receptor expression in brain to determine the mechanism by which iron is obtained in oligodendrocytes is warranted.

The ratio of H/L ferritin in the brain also differs with cell type. Neurons contain predominantly H-ferritin, microglia contain predominantly L-ferritin, and oligodendrocytes contain a mixture of both ferritin subunits (Connor and Menzies, 1995; Connor et al., 1994). Astrocytes in general do not contain ferritin except in mice (Dickinson and Connor, 1995) and in the human striatum (an iron-rich area), where the astrocytes immunostain intensely for L-ferritin subunits (Connor, 1994). The differential cellular distribution of H- and L-ferritin indicates that neurons have a high iron requirement with little capacity to store iron, whereas the predominance of L-ferritin in microglia is consistent with their role as scavenger cells. The only cells to contain a mixture of H- and L-ferritin are oligodendrocytes, which suggests both a high level of intracellular iron and a relatively high utilization rate for iron. The absence of ferritin in most astrocytes indicates that these cells have little to do with iron regulation except in the iron-rich striatum, where they must play a role in sequestering iron.

As a result of its ability to sequester iron rapidly, the H-ferritin subunit is considered a crytoprotectant (Balla et al., 1992) because iron removed rapidly by this protein is not available for inducing oxidative damage. However, there is evidence that iron can be removed from ferritin by a number of reducing agents; thus sequestration of iron in ferritin does not preclude the possibility of iron-induced oxidative damage. H-ferritin appears to have a protective role in oligodendrocytes physiology; H-ferritin synthesis increased in oligodendrocytes following exposure to hypoxic conditions and returned to normal when the cells were returned to normoxic conditions (Qi and Dawson, 1994). Also, H-ferritin in oligodendrocytes is increased by exposure to tumor necrosis factor æ (TNFæ) (Sanyal and Szuchet, 1995), further indicating a crytoprotective role for H-ferritin in theses cells. The vulnerability of oligodendrocytes to oxidative damage and the expression of H-ferritin are likely linked; this is a fruitful area for further study.

No studies have examined the developmental expression of ferritin subunits in brain (or other organs to our knowledge). Our initial analyses indicate that H-ferritin but not L-ferritin is expressed in the earliest stages of oligodendrocyte development (Blissman et al., 1996, submitted). H-ferritin cells are found aligning blood vessels and in clusters interspersed throughout the white matter, whereas L-ferritin is predominantly associated with endothelial cells (Fig. 4A, B). That the H-ferritin-positive cells are oligodendrocytes has been confirmed by co-localization with 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNPase), a standard marker for oligodendrocytes in the white matter tracts than H-ferritin-containing cells, and the CNPase-positive cells are distributed homogeneously throughout the white matter tract. These co-localization results indicate that there is a subset of oligodendrocytes that express H-ferritin and accumulate iron. This subset of oligodendrocytes appears to increase in number but continues to persist as a subset into adulthood (Connor and Menzies, 1995).

The H-ferritin-positive oligodendrocytes are frequently but not always the oligodendrocytes more closely associated with blood vessels, suggesting that iron transported across the blood-brain barrier accumulates preferentially in these cells. There is a report that myelinogenesis begins in the vicinity of blood vessels (Skoff et al., 1980), and we have evidence that iron accumulation in oligodendrocytes and myelin production are coincident . The role of iron in the maturation of these ferritin/iron-rich subset of oligodendrocytes, the relationship of these cells to myelin production and maintenance, and the relative vulnerability to oxidative stress of these cells to non-iron-rich oligodendrocytes remain to be determined it is clear from these studies that there is a subset of oligodendrocytes in white matter tracts that can be distinguished by ferritin and iron accumulation.

The analysis of ferritin subunit expression in brain at the mRNA level has just begun. H-ferritin mRNA is expressed in cerebral cortex in both gray and white matter in the 30-day-old rat (Fig. 5), but white matter tracts such as the medial longitudinal fasciculus, cerebellar peduncles, and pyramidal tracts clearly express higher levels of H-ferritin mRNA than the surrounding gray matter.

We have discussed the importanceof iron and iron management by oligodendrocytes for normal myelination. What about a potential role for iron in demyelinating disorders? The vulnerability of oligodendrocytes to oxidative stress has already been addressed. Another area in which disruption of iron acquisition by oligodendrocytes could be associated with demyelination is in the relationship between cytokines and demyelinating disorders; some of the effects of cytokines on myelination could be mediated through modification of cellular iron acquisition. A considerable literature exists regarding the relationship between parameters of iron metabolism and cytokine influence on immune system function Dhur et al., 1989). Both T-cell proliferation and lymphokine release are iron dependent (Brock and Stevenson, 1987), and the immune system is depressed in iron deficiency (Kuvibidila et al., 1990). Tf receptor expression by lymphocytes is stimulated by interleukin 2 (weinberg, 1989). In macrophages, iron upregulates Tf receptors rather than decreasing them in the expected negative feedback fashion (Testa et al., 1989). Furthermore, macropages are capable of removing iron from other cells without causing lysis or cell death (Drapier and Hibbs, 1986; Hibbs et al., 1984). Thus, macrophages infiltrating into multiple sclerosis lesions would find a ready supply of iron in oligodendrocytes and would also secrete cytokines and reactive metabolites of oxygen, both of which would be harmful to oligodendrocytes (Guilian, 1987; Takemura and Werb, 1984). These ideas are consistent with the findings that activated macrophages are associated with multiple sclerosis lesions and may stimulate myelin breakdown (Fisher et al., 1988; Johnson et al., 1989). Specific cytokines such as interleukin-2, interleukin-6, and TNF, which are secreted by microglia and macrophages, decrease secretion of Tf from Sertoli cells (Boockfor and Schwarz, 1991) and could have the same effect on oligodendrocytes, limiting their ability to acquire sufficient iron for remyelination. Our data on Hp mice suggest that secretion of Tf by oligodendrocytes is essential for normal myelin production (Dickinson and Connor, 1985) The effect of cytokines on glial function and specifically a possible role of cytokines on multiple sclerosis are active areas of investigation. The importance of iron in myelin production and the clearly established effects of cytokines in iron metabolism in non-neural cells suggest that the relationship between cytokines and iron acquisition by oligodendrocytes could be a potentially fruitful area of investigation.

In summary, oligodendrocytes have a high dependability on iron availability for normal function. Consequently, the proteins involved in intracellular iron management are enriched in these cells in the adult, and their appearance in these cells during development precedes myelin associated markers. Disruption in the availability of iron impeded myelination both in the adult and during development and may impede attempts at remyelination in disease. The high iron requirement of oligodendrocytes is likely responsible for the vulnerability of these cells to oxidative stress, although specific protective mechanisms such as increased production of H-chain ferritin are in place.

The presence of a thriving population of oligodendrocytes is necessary for Tf and its mRNA and the Tf receptor to be expressed in normal levels in brain, but not for brain iron uptake. Synthesis of Tf by oligodendrocytes is not necessary for their survival, but hypomyelination is associated with lack of brain-produced Tf. The hypomyelination in the absence of brain Tf may stem from insufficient levels of iron reaching the oligodendrocytes.

We propose that Tf produced by oligodendrocytes has an autocrine role and is secreted to help these cells acquire iron. Tf secretion by oligodendrocytes has been demonstrated in cell culture studies (Espinosa de los Monteros et al., 1990), but the conditions controlling Tf secretion have not been pursued.

Finally, a lack of overlap between transferrin-positive cells and ferritin-iron-positive cells in white matter during development and the adult is consistently seen. Both of these cells have the morphological appearance of oligodendrocytes and both are CNPase positive, which has led to the interpretation that there is a subset of olugodendrocytes in white matter tracts. Tf-positive cells are generally not associated with blood vessels in the white matter, so they may be in a constant state of iron deprivation and may synthesize and secrete Tf to acquire iron.

alternatively, the Tf-positive cells could be a subset of oligodendrocytes that synthesize and secrete Tf for iron mobilization within the central nervous system. This idea has been raised by Espinosa de los Monteros and de Vellis (1988) from tissue culture studies of enriched oligodendrocytes in which a transferrin-positive myelin basic protein-negative subpopulation of cells was observed. The abundance of iron/ferritin cells in white matter makes it difficult to argue that these cells would be a separate non-myelinating population of oligodendrocytes that possibly function as an iron regulatory population of cells. Regardless of the outcome of the subpopulation issues Raised in this review, the abundance of Tf and H-ferritin mRNAs in white matter supports the idea of a dynamic population of cells that are continuously involved in mobilization of iron either intracellularly or extracellularly and suggests a dynamic process of iron acquisitionand utilization in white matter that is likely to influence myelination.

The work reported in this review was supported by USPHS grants NS 22671, AG09063, and HD30704 and the National Multiple Sclerosis Society.

A complete set of references will follow here as soon as they can be typed.