Neuregulin: An Oligodendrocyte Growth Factor Absent in Active Multiple Sclerosis Lesions

Viehöver, Andrea; Miller, Robert H.; Park, Song Kyu; Fischbach, Gerald D.; Vartanian, Timothy

doi:10.1159/000048721

Cited by 64 publications

(35 citation statements)

References 48 publications

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“…Neuregulins have been shown to be necessary for oligodendrocyte development and to promote the proliferation and survival of OPCs while blocking OPC differentiation; however, this latter effect is dependent on the stage of development of the OPC (Canoll et al, 1996;Viehover et al, 2001). Interestingly, in the active and chronic MS lesion, expression of neuregulin by astrocytes is significantly decreased and has been suggested to contribute to the lack of remyelination that is observed in MS (Viehover et al, 2001).…”

Section: Bone Morphogenic Proteinsmentioning

confidence: 99%

How factors secreted from astrocytes impact myelin repair

Moore

Abdullah

Brown

et al. 2010

J of Neuroscience Research

139

117

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Over a century ago, hypertrophy of astrocytes was noted as a pathology of multiple sclerosis (MS) and was hypothesized to play an important role in this disease, yet the contribution of astrocytes has been largely underemphasized in the pathophysiology of CNS demyelination. Astrocytes perform many homeostatic functions within the developing and adult CNS, including enhancing formation and maintenance of the blood-brain barrier, moderating neuronal connections through the tripartite synapse, and perhaps even offering intercellular communication independently of neurons. Although there is a significant body of literature characterizing different types of MS lesions, the inflammatory demyelination in an active MS lesion is accompanied by the presence of macrophages, lymphocytes, and large reactive astrocytes. The astrocyte has long been viewed as a cell that promotes inflammation and demyelination, while also forming the glial scar, thus hindering remyelination and axon growth. Renewed interest in the astrocyte has been brought about by recent studies demonstrating that astrocytes can also function as cellular mediators of CNS myelination by promoting oligodendrocyte progenitor migration, proliferation, and differentiation. Thus, refining our knowledge of astrocytic functions in the regulation of CNS myelination may help us to better understand why remyelination fails in MS.

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Section: Bone Morphogenic Proteinsmentioning

confidence: 99%

How factors secreted from astrocytes impact myelin repair

Moore

Abdullah

Brown

et al. 2010

J of Neuroscience Research

139

117

View full text Add to dashboard Cite

show abstract

“…In MS lesions, persistence of immature oligodendrocyte lineage cells may indicate inhibition of differentiation by local signals, especially those associated with astrocytic scar formation, such as FGF2 [47][48][49][50]. Conversely, signals that are beneficial for oligodendrocyte maturation may not be present at sufficient levels, as has been proposed for neuregulin [51]. The inflammatory response may also modulate oligodendrocyte differentiation in lesions.…”

Section: Modifying the Balance Of Signals Regulating Op Differentiationmentioning

confidence: 99%

Growth factor regulation of remyelination: behind the growing interest in endogenous cell repair of the CNS

Armstrong

2007

Future Neurol.

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Remyelination facilitates recovery of saltatory conduction along demyelinated axons and may help prevent axon damage in patients with demyelinating diseases, such as multiple sclerosis. The extent of remyelination in multiple sclerosis lesions varies dramatically, indicating a capacity for repair that is not fulfilled in lesions with poor remyelination. In experimental models of demyelinating disease, remyelination is limited by chronic disease that depletes the oligodendrocyte progenitor (OP) population, inhibits OP differentiation into remyelinating oligodendrocytes and/or perturbs cell survival in the lesion environment. Manipulating the activity of growth factor signaling pathways significantly improves the ability of endogenous OP cells to accomplish extensive remyelination. Specifically, growth factors have been identified that can regulate OP proliferation, differentiation and survival in demyelinated lesions. Therefore, growth factors may be key signals for strategies to improve conditions with poor remyelination. Keywords cuprizone; demyelinating disease; FGF; multiple sclerosis; myelin; oligodendrocyte; PDGF; progenitors; remyelination Transition to in vivo analysis during remyelinationAnalysis of growth factors to promote repair in demyelinating diseases has undergone an important transition to in vivo studies and in doing so has revealed much more than the expected results. Characterization of the bipotential oligodendrocyte-type 2 astrocyte or oligodendrocyte progenitor (OP) cell, and the regulation of cell fate by serum components [1] opened the door for in vitro analysis of growth factor responses in the oligodendrocyte lineage. Numerous subsequent in vitro studies identified specific growth factors capable of regulating differentiation, proliferation, migration and survival at specific stages within this lineage. In vitro studies continue to offer distinct advantages for isolating molecular and cellular mechanisms of action and for characterizing the potential of defined growth factors to induce a specific cellular response. In this context, several cytokines and chemokines have been identified as having direct effects on oligodendrocyte lineage cells that are similar to growth factor actions and so they will be discussed together under the rubric of growth factors. This review will focus on recent in vivo remyelination studies designed to test potential growth factor responses identified in vitro. These in vivo studies demonstrate important effects of growth factors in the context of demyelinating disease models in rodents. However, not all growth factor analyses have resulted in the predicted responses. Importantly, several studies have demonstrated a remarkable capacity of endogenous cells to repair the adult CNS, even following chronic demyelination, using modulation of growth factor signaling to better support oligodendrocyte replacement and myelin formation.

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“…phosphorylation) of insulin growth factor receptor and epidermal growth factor receptor (a member of the Erb family of receptor tyrosine kinases) and by Src kinases such as Fyn (37). Although the expression of epidermal growth factor receptor is down-regulated in OLs upon terminal differentiation, in mature OLs, high levels of ErbB2 tyrosine kinase are maintained (41), and ErbB2 is necessary for normal OL differentiation and survival; further, the astrocytic expression of ErbB2 is reduced in multiple sclerosis lesions (42). However, the examination of the effect of MOG cross-linking on these receptors showed that neither insulin growth factor receptor nor ErbB2 phosphorylation was altered (Fig.…”

Section: Identification Of Proteinsmentioning

confidence: 99%

Signaling Cascades Activated upon Antibody Cross-linking of Myelin Oligodendrocyte Glycoprotein

Marta

Montano

Taylor

et al. 2005

Journal of Biological Chemistry

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Antibody-induced demyelination is an important component of pathology in multiple sclerosis. In particular, antibodies to myelin oligodendrocyte glycoprotein (MOG) are elevated in multiple sclerosis patients, and they have been implicated as mediators of demyelination. We have shown previously that antibody crosslinking of MOG in oligodendrocytes results in the repartitioning of MOG into glycosphingolipid-cholesterol membrane microdomains ("lipid rafts"), followed by changes in the phosphorylation of specific proteins, including dephosphorylation of ␤-tubulin and the ␤ subunit of the trimeric G protein and culminating in rapid and dramatic morphological alterations. In order to further elucidate the mechanism of anti-MOG-mediated demyelination, we have carried out a proteomic analysis to identify the set of proteins for which the phosphorylation states or expression levels are altered upon anti-MOG treatment. We demonstrate that treatment of oligodendrocytes with anti-MOG alone leads to an increase in calcium influx and activation of the MAPK/Akt pathways that is independent of MOG repartitioning. However, further cross-linking of anti-MOG⅐MOG complexes with a secondary anti-IgG results in the lipid raft-dependent phosphorylation of specific proteins related to cellular stress response and cytoskeletal stability. Oligodendrocyte survival is not compromised by these treatments. We discuss the possible significance of the anti-MOG-induced signaling cascade in relation to the initial steps of MOG-mediated demyelination.The investigation of the transfer of information between myelin and axons is at the forefront of myelin biology and demyelinating disease (1-3). Loss or damage of myelin, such as occurs in the human demyelinating disease multiple sclerosis, results in axonal degeneration with severe, generally irreversible, functional consequences (4). Multiple sclerosis-related demyelination is in part induced by antibodies directed against surface antigens of myelin and oligodendrocytes (OLs), 1 the myelin-producing cells of the central nervous system (5). In particular, antibodies to myelin oligodendrocyte glycoprotein (MOG), a highly encephalitogenic glycoprotein concentrated in the outer lamella of the myelin sheath and thus exposed to the environment (6), have been implicated as mediators of demyelination (7-10).Upon ligand or antibody cross-linking, a variety of plasma membrane receptors undergo enhanced partitioning into glycosphingolipid-cholesterol membrane microdomains ("lipid rafts") as an obligatory first step toward participation in early signal transduction events (11-13). We have previously shown that antibody cross-linking of MOG on the surface of OLs results in the rapid repartitioning of a significant fraction of MOG into lipid rafts, followed by dephosphorylation of ␤-tubulin and the ␤ subunit of the trimeric G protein (G␤), and a rapid retraction of OL processes and myelin-like membranes (14). In order to elucidate this mechanism and better consider its relationship to antibody-mediated demyelina...

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Neuregulin: An Oligodendrocyte Growth Factor Absent in Active Multiple Sclerosis Lesions

Cited by 64 publications

References 48 publications

How factors secreted from astrocytes impact myelin repair

How factors secreted from astrocytes impact myelin repair

Growth factor regulation of remyelination: behind the growing interest in endogenous cell repair of the CNS

Signaling Cascades Activated upon Antibody Cross-linking of Myelin Oligodendrocyte Glycoprotein

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