Alterations in metabolism and gene expression in brain regions during cuprizone‐induced demyelination and remyelination

Jurevics, Helga; Largent, Carrie; Hostettler, Janell; Sammond, Deanne W.; Matsushima, Glenn K.; Kleindienst, Amber M.; Toews, Arrel D.; Morell, Pierre

doi:10.1046/j.1471-4159.2002.00954.x

Cited by 97 publications

(93 citation statements)

References 50 publications

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“…Several studies have applied microarray analysis to investigate gene expression changes associated with de-myelination and remyelination (Arnett et al, 2003;Jurevics et al, 2002;Morell et al, 1998). These studies were, however, to a certain extent tainted by the use of whole tissue lysates.…”

Section: Discussionmentioning

confidence: 99%

Identification of a microglia phenotype supportive of remyelination

Olah

Amor

Brouwer

et al. 2011

Glia

314

270

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In multiple sclerosis, endogenous oligodendrocyte precursor cells (OPCs) attempt to remyelinate areas of myelin damage. During disease progression, however, these attempts fail. It has been suggested that modulating the inflammatory environment of the lesion might provide a promising therapeutic approach to promote endogenous remyelination. Microglia are known to play a central role in neuroinflammatory processes. To investigate the microglia phenotype that supports remyelination, we performed genome-wide gene expression analysis of microglia from the corpus callosum during demyelination and remyelination in the mouse cuprizone model, in which remyelination spontaneously occurs after an episode of toxin-induced primary demyelination. We provide evidence for the existence of a microglia phenotype that supports remyelination already at the onset of demyelination and persists throughout the remyelination process. Our data show that microglia are involved in the phagocytosis of myelin debris and apoptotic cells during demyelination. Furthermore, they express a cytokine and chemokine repertoire enabling them to activate and recruit endogenous OPCs to the lesion site and deliver trophic support during remyelination. This study not only provides a detailed transcriptomic analysis of the remyelinationsupportive microglia phenotype but also reinforces the notion that the primary function of microglia is the maintenance of tissue homeostasis and the support of regeneration already at the earliest stages in the development of demyelinating lesions. V

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Section: Discussionmentioning

confidence: 99%

Identification of a microglia phenotype supportive of remyelination

Olah

Amor

Brouwer

et al. 2011

Glia

314

270

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“…Thus the chelation of copper causes demyelination and an upregulation of IGF-1. 43 Vitamin B12 deficiency 44 and chronic nitrous oxide exposure, 45 both of which impair MS, also cause demyelination. We found that Cu 2 þ promotes MS activity (Table 1) and protects against the inhibitory effects of other metals (Figure 5e), while Cu 2 þ chelation has an opposite effect (Figures 5a and f).…”

Section: Igf-1 and Dopamine Regulate Methionine Synthase M Waly Et Almentioning

confidence: 99%

Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal

et al. 2004

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Methylation events play a critical role in the ability of growth factors to promote normal development. Neurodevelopmental toxins, such as ethanol and heavy metals, interrupt growth factor signaling, raising the possibility that they might exert adverse effects on methylation. We found that insulin-like growth factor-1 (IGF-1)-and dopamine-stimulated methionine synthase (MS) activity and folate-dependent methylation of phospholipids in SH-SY5Y human neuroblastoma cells, via a PI3-kinase-and MAP-kinase-dependent mechanism. The stimulation of this pathway increased DNA methylation, while its inhibition increased methylationsensitive gene expression. Ethanol potently interfered with IGF-1 activation of MS and blocked its effect on DNA methylation, whereas it did not inhibit the effects of dopamine. Metal ions potently affected IGF-1 and dopamine-stimulated MS activity, as well as folate-dependent phospholipid methylation: Cu 2 þ promoted enzyme activity and methylation, while Cu þ , Pb 2 þ , Hg 2 þ and Al 3 þ were inhibitory. The ethylmercury-containing preservative thimerosal inhibited both IGF-1-and dopamine-stimulated methylation with an IC 50 of 1 nM and eliminated MS activity. Our findings outline a novel growth factor signaling pathway that regulates MS activity and thereby modulates methylation reactions, including DNA methylation. The potent inhibition of this pathway by ethanol, lead, mercury, aluminum and thimerosal suggests that it may be an important target of neurodevelopmental toxins.

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“…An alternative to genetic screening is to use recently developed gene profiling methods. Previous gene profiling studies of OPCs and OLs have focused on either the process of demyelination versus remyelination in CNS tissue derived from cuprizonedemyelinated animals (Jurevics et al, 2002;Arnett et al, 2003), or on the differences between uncommitted neural precursors and OPCs (Hu et al, 2004), as opposed to the terminal differentiation step of primary OPCs into mature OLs.…”

Section: Introductionmentioning

confidence: 99%

Functional Genomic Analysis of Oligodendrocyte Differentiation

Dugas¹,

Tai²,

Speed³

et al. 2006

J. Neurosci.

294

353

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To better understand the molecular mechanisms governing oligodendrocyte (OL) differentiation, we have used gene profiling to quantitatively analyze gene expression in synchronously differentiating OLs generated from pure oligodendrocyte precursor cells in vitro. By comparing gene expression in these OLs to OLs generated in vivo, we discovered that the program of OL differentiation can progress normally in the absence of heterologous cell-cell interactions. In addition, we found that OL differentiation was unexpectedly prolonged and occurred in at least two sequential stages, each characterized by changes in distinct complements of transcription factors and myelin proteins. By disrupting the normal dynamic expression patterns of transcription factors regulated during OL differentiation, we demonstrated that these sequential stages of gene expression can be independently controlled. We also uncovered several genes previously uncharacterized in OLs that encode transmembrane, secreted, and cytoskeletal proteins that are as highly upregulated as myelin genes during OL differentiation. Last, by comparing genomic loci associated with inherited increased risk of multiple sclerosis (MS) to genes regulated during OL differentiation, we identified several new positional candidate genes that may contribute to MS susceptibility. These findings reveal a previously unexpected complexity to OL differentiation and suggest that an intrinsic program governs successive phases of OL differentiation as these cells extend and align their processes, ensheathe, and ultimately myelinate axons.

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Alterations in metabolism and gene expression in brain regions during cuprizone‐induced demyelination and remyelination

Cited by 97 publications

References 50 publications

Identification of a microglia phenotype supportive of remyelination

Identification of a microglia phenotype supportive of remyelination

Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal

Functional Genomic Analysis of Oligodendrocyte Differentiation

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