Neonatal Oligodendrocytes Contain and Secrete Neuregulins In Vitro

Raabe, Timothy D.; Clive, Diana R.; Wen, Duanzhi; DeVries, George H.

doi:10.1046/j.1471-4159.1997.69051859.x

Cited by 50 publications

(32 citation statements)

References 22 publications

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“…OLs use other autocrine signaling mechanisms. For example, developing OLs regulate their own survival and differentiation via the neuregulin-erbB receptor autocrine loop (45,46), and galanin was identified as an autocrine trophic signal in cytokine-treated OLs and in the cuprizone-induced demyelination model (47). The HMBG1-mediated autocrine trophic signaling evidenced in our study may harnesses neighboring OLs with a sort of self-defense system against ischemic injuries to the white matter.…”

Section: Discussionmentioning

confidence: 57%

High-mobility group box-1 as an autocrine trophic factor in white matter stroke

Choi

Cui

Chowdhury

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Maintenance of white matter integrity in health and disease is critical for a variety of neural functions. Ischemic stroke in the white matter frequently results in degeneration of oligodendrocytes (OLs) and myelin. Previously, we found that toll-like receptor 2 (TLR2) expressed in OLs provides cell-autonomous protective effects on ischemic OL death and demyelination in white matter stroke. Here, we identified high-mobility group box-1 (HMGB1) as an endogenous TLR2 ligand that promotes survival of OLs under ischemic stress. HMGB1 rapidly accumulated in the culture medium of OLs exposed to oxygen-glucose deprivation (OGD). This conditioned medium exhibited a protective activity against ischemic OL death that was completely abolished by immunodepletion of HMGB1. Knockdown of HMGB1 or application of glycyrrhizin, a specific HMGB1 inhibitor, aggravated OGD-induced OL death, and recombinant HMGB1 application reduced the extent of OL death in a TLR2-dependent manner. We confirmed that cytosolic translocation of HMGB1 and activation of TLR2-mediated signaling pathways occurred in a focal white matter stroke model induced by endothelin-1 injection. Animals with glycyrrhizin coinjection showed an expansion of the demyelinating lesion in a TLR2-dependent manner, accompanied by aggravation of sensorimotor behavioral deficits. These results indicate that HMGB1/ TLR2 activates an autocrine trophic signaling pathways in OLs and myelin to maintain structural and functional integrity of the white matter under ischemic conditions. white matter stroke | oligodendrocyte | toll-like receptor 2 | HMGB1 | myelination W hite matter in the vertebrate brain is characterized by the presence of myelinated axonal fibers and glial cells, predominantly myelin-producing oligodendrocytes (OLs) (1). The myelin sheath enables rapid communication of neural signals at a millisecond timescale between different parts of the cerebral cortex or different regions of the CNS (2). Therefore, maintaining the integrity of white matter in health and disease, especially of OLs and the myelin sheath, is critical to the performance of a variety of brain functions. Furthermore, recent studies have shown that myelination and OL generation in adulthood are actively regulated in response to neural activities (3, 4), highlighting the potential contribution of white matter plasticity to learning and higher cognitive functions.Ischemic stroke that occurs in the white matter often results in degeneration of OLs and demyelination (5, 6). Consequently, patients with white matter stroke suffer from a wide range of neurological dysfunctions. For example, focal ischemic stroke in the internal capsule may result in severe hemiparesis (7). Furthermore, both cognitive deficits and gait disturbance are hallmarks of Binswanger's subcortical vascular dementia that is the most severe form of white matter stroke (8). How ischemia leads to OL degeneration and demyelination is poorly understood. We previously reported that toll-like receptor 2 (TLR2) expressed in OLs plays a protect...

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Section: Discussionmentioning

confidence: 57%

High-mobility group box-1 as an autocrine trophic factor in white matter stroke

Choi

Cui

Chowdhury

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Not only is NRG-1 and various ErbB receptors expressed in the subependymal zone and the forebrain oligogenic zone, but NRG-1 can also induce the division 43 and/or promote the differentiation of oligodendrocyte precursors in vitro. [44][45][46][47] It is conceivable that relatively decreased type II mRNA expression may relate to putative abnormalities of oligodendroglial function implicated in schizophrenia. 48,49 Finally, we did not find evidence that NRG-1 type III mRNA expression levels are changed in schizophrenia DLPFC, although this isoform also has effects on neuronal plasticity and development.…”

Section: Discussionmentioning

confidence: 99%

Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia

et al. 2003

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Genetic linkage and association have implicated neuregulin-1 (NRG-1) as a schizophrenia susceptibility gene. We measured mRNA expression levels of the three major isoforms of NRG-1 (ie type I, type II, and type III) in the postmortem dorsolateral prefrontal cortex (DLPFC) from matched patients and controls using real-time quantitative RT-PCR. Expression levels of three internal controls-GAPDH, cyclophilin, and b-actin-were unchanged in schizophrenia, and there were no changes in the absolute levels of the NRG-1 isoforms. However, type I expression normalized by GAPDH levels was significantly increased in schizophrenia DLPFC (by 23%) and positively correlated with antipsychotic medication dosage. Type II/type I and type II/type III ratios were significantly decreased (18 and 23% respectively). There was no effect on the NRG-1 mRNA levels of genotype at two SNPs previously associated with schizophrenia, suggesting that these alleles are not functionally responsible for abnormal NRG-1 expression patterns in patients. Subtle abnormalities in the expression patterns of NRG-1 mRNA isoforms in DLPFC may be associated with schizophrenia.

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“…The neuregulin/erbB receptor system seems an ideal candidate to provide survival signals for oligodendrocytes in vivo. In the CNS, neurons, oligodendrocytes, and astrocytes both produce neuregulins and express neuregulin receptors (Chen et al, 1994;Meyer and Birchmeier, 1994;Raabe et al, 1997a;Francis et al, 1999). Furthermore, neuregulins present on the surface of axons play a role in the maintenance of oligodendrocytes and their progenitors (Canoll et al, 1996;Vartanian et al, 1997).…”

Section: Abstract: Oligodendrocyte; Survival; Akt; Neuregulin; Multimentioning

confidence: 99%

Akt-Mediated Survival of Oligodendrocytes Induced by Neuregulins

et al. 2000

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Neuregulins have been implicated in a number of events in cells in the oligodendrocyte lineage, including enhanced survival, mitosis, migration, and differentiation. At least two signaling pathways have been shown to be involved in neuregulin signaling: the phosphatidylinositol (PI)-3 kinase and the mitogen-activated protein kinase pathways. In the present studies, we examined the signaling pathway involved in the survival function of heregulin, focusing on heregulin-induced changes in Akt activity in cultured glial cells, and the consequences of Akt activation in cells in the oligodendrocyte lineage. Heregulin binds erbB receptors, and in our studies, primary cultures of both oligodendrocyte progenitor cells and differentiating oligodendrocytes expressed erbB2, erbB3, and erbB4 receptors. In C6 glioma cells and primary cultures of oligodendrocytes, heregulin induced time-and dosedependent Akt phosphorylation at Ser 473 in a wortmanninsensitive manner. To investigate further the signaling pathway for heregulin in glial cells, BAD was overexpressed in C6 glioma cells. In these cells, heregulin induced phosphorylation of BAD at Ser 136 . Apoptosis of oligodendrocyte progenitor cells induced by growth factor deprivation was effectively blocked by heregulin in a wortmannin-sensitive manner. Overexpression of dominant negative Akt but not of wild-type Akt by adenoviral gene transfer in primary cultures of both oligodendrocytes and their progenitors induced significant apoptosis through activation of the caspase cascade. The present data suggest that the survival function of heregulin is mediated through the PI-3 kinase/Akt pathway in cells in the oligodendrocyte lineage and that the Akt pathway may be quite important for survival of cells in this lineage.

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Neonatal Oligodendrocytes Contain and Secrete Neuregulins In Vitro

Cited by 50 publications

References 22 publications

High-mobility group box-1 as an autocrine trophic factor in white matter stroke

High-mobility group box-1 as an autocrine trophic factor in white matter stroke

Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia

Akt-Mediated Survival of Oligodendrocytes Induced by Neuregulins

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