mTOR: A Link from the Extracellular Milieu to Transcriptional Regulation of Oligodendrocyte Development

Wood, Teresa L.; Bercury, Kathryn K.; Cifelli, Stacey E.; Mursch, Lauren E.; Min, Jungsoo; Dai, Jinxiang; Macklin, Wendy B.

doi:10.1042/an20120092

Cited by 62 publications

(57 citation statements)

References 203 publications

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“…mTOR plays an important role in cell growth under normal conditions and in neuroprotection under H/I conditions in the developing brain. In addition, mTOR along with Akt has been highlighted as one of the pathways involved in the differentiation of oligodendrocytes and development of myelination [18]. However, little is known about the role of the mTOR signaling pathways that protect the nervous system after EPO treatment in neonates with H/I brain injury.…”

Section: Discussionmentioning

confidence: 99%

The Akt/mTOR/p70S6K Pathway Is Involved in the Neuroprotective Effect of Erythropoietin on Hypoxic/Ischemic Brain Injury in a Neonatal Rat Model

Lee

Koh²,

Song

et al. 2016

Neonatology

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Background: The mTOR (mammalian target of rapamycin) signaling pathway is a master regulator of cell growth and proliferation in the nervous system. However, the effects of erythropoietin (EPO) treatment on the mTOR signaling pathway have not been elucidated in neonates with hypoxic/ischemic (H/I) brain injury. Objectives: We investigated the mechanism underlying the neuroprotective effect of EPO by analyzing the mTOR signaling pathway after H/I injury in a neonatal rat model. Methods: Seven-day-old rats were subjected to left carotid artery ligation and hypoxic exposure (8%) for 90 min (H/I). EPO at a dose of either 3,000 U/kg or a vehicle (V) was administered by intraperitoneal injection 0, 24 and 48 h after H/I. At 72 h after H/I (postnatal day 10), 2,3,5-triphenyltetrazolium chloride staining, myelin basic protein (MBP) immunofluorescence staining and Western blot analysis of the Akt/mTOR/p70S6K pathway were performed. Neuromotor behavioral tests included Rotarod challenge and cylinder rearing test 1 performed 3 and 6 weeks after H/I. Results: EPO treatment resulted in significant offsetting of MBP depletion ipsilateral (p = 0.001) and contralateral (p = 0.003) to ligation. Western blot analysis showed that the relative immunoreactivity of phosphorylated (p)-Akt, p-mTOR and p-p70S6K ipsilateral to ligation was significantly decreased in the H/I+V group compared with the sham-operated groups. However, EPO treatment significantly upregulated Akt/mTOR/p70S6K signals ipsilateral to ligation compared to the H/I+V group. The behavior tests showed that EPO attenuates long-term impairment in Rotarod challenge and cylinder test performance from 3-6 weeks. Conclusion: This study demonstrates an underlying mechanism of the mTOR signaling pathway after EPO treatment, which is a potential target for treating H/I-induced brain injury.

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Section: Discussionmentioning

confidence: 99%

The Akt/mTOR/p70S6K Pathway Is Involved in the Neuroprotective Effect of Erythropoietin on Hypoxic/Ischemic Brain Injury in a Neonatal Rat Model

Lee

Koh²,

Song

et al. 2016

Neonatology

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“…1B). The AKT/mTOR signaling pathway has been implicated in many aspects of OL development including OPC proliferation, migration, survival, differentiation, and myelination (reviewed in detail by (Norrmen and Suter, 2013; Wood et al, 2013). Below, we focus on evidence for the importance of AKT/mTOR during OPC differentiation, myelination, and remyelination.…”

Section: Akt/mtor Signaling Pathwaymentioning

confidence: 99%

“…Recent studies have focused on whether these pathways function independently, sequentially, or whether crosstalk between them is important for mediating their effects on OL development and myelination through a common mechanism. Outside of the field of myelination, particularly in the field of cancer research, ERK and AKT pathways are thought to be part of a complex signaling network with multiple points of crosstalk (Aksamitiene et al, 2012; Wood et al, 2013). In tuberous sclerosis, a tumor syndrome caused by mutations in TSC1 or TSC2 genes, both ERK1/2 and AKT are thought to contribute to disease progression since they can each independently phosphorylate and inactivate TSC2 at distinct residues, resulting in the activation of mTORC1 (Ma et al, 2005).…”

Section: Crosstalkmentioning

confidence: 99%

“…OL-specific knockout of Erk2 resulted in delayed MBP translation and decreased activation of p70S6K and its downstream target S6RP, both important regulators of translation, during a critical window when pre-myelinating OLs were transitioning to mature OLs capable of generating new myelin sheaths (Michel et al, 2015). Importantly, the activation of mTOR, a classical regulator of p70S6K (Lebrun-Julien et al, 2014; Wood et al, 2013) was seemingly unaffected by the loss of ERK2. These data led us to propose a model where the appropriate timing of MBP protein expression during remyelination requires a critical threshold of p70S6K activation that is achieved only after the coordinated activation of both ERK/MAPK and AKT/mTOR pathways.…”

Section: Crosstalkmentioning

confidence: 99%

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Intracellular signaling pathway regulation of myelination and remyelination in the CNS

Gaesser

Fyffe-Maricich

2016

Experimental Neurology

158

127

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The restoration of myelin sheaths on demyelinated axons remains a major obstacle in the treatment of multiple sclerosis (MS). Currently approved therapies work by modulating the immune system to reduce the number and rate of lesion formation but are only partially effective since they are not able to restore lost myelin. In the healthy CNS, myelin continues to be generated throughout life and spontaneous remyelination occurs readily in response to insults. In patients with MS, however, remyelination eventually fails, at least in part as a result of a failure of oligodendrocyte precursor cell (OPC) differentiation and the subsequent production of new myelin. A better understanding of the molecular mechanisms and signaling pathways that drive the process of myelin sheath formation is therefore important in order to speed the development of novel therapeutics designed to target remyelination. Here we review data supporting critical roles for three highly conserved intracellular signaling pathways: Wnt/β-catenin, PI3K/AKT/mTOR, and ERK/MAPK in the regulation of OPC differentiation and myelination both during development and in remyelination. Potential points of crosstalk between the three pathways and important areas for future research are also discussed.

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“…Reduced levels of BDNF, OPCs, and myelin proteins were observed in transgenic mice heterozygous for BDNF [71, 98]. The association of estrogens with IGF-1R/Trk-B through the PI3K/Akt/mTOR signaling pathway may illustrate the point of convergence between estrogen and IGF-1/BDNF to promote OPC proliferation, OL differentiation, and survival after demyelination [38, 71, 99]. Estrogen ligands that successfully activate these pathways to initiate OPC/OL survival, OL differentiation, and axon myelination would be most effective in prompting remyelination and neuroprotection.…”

Section: Estrogens and Oligodendrocytesmentioning

confidence: 99%

Nudging oligodendrocyte intrinsic signaling to remyelinate and repair: Estrogen receptor ligand effects

Khalaj

Hasselmann

Augello

et al. 2016

The Journal of Steroid Biochemistry and Molecular Biology

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Demyelination in multiple sclerosis (MS) leads to significant, progressive axonal and neuronal degeneration. Currently existing immunosuppressive and immunomodulatory therapies alleviate MS symptoms and slow, but fail to prevent or reverse, disease progression. Restoration of damaged myelin sheath by replenishment of mature oligodendrocytes (OLs) should not only restore saltatory axon conduction, but also provide a major boost to axon survival. Our previous work has shown that therapeutic treatment with the modestly selective generic estrogen receptor (ER) β agonist diarylpropionitrile (DPN) confers functional neuroprotection in a chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS by stimulating endogenous myelination. Recently, we found that the more potent, selective ERβ agonist indazole-chloride (Ind-Cl) improves clinical disease and motor performance. Importantly, electrophysiological measures revealed improved corpus callosal conduction and reduced axon refractoriness. This Ind-Cl treatment-induced functional remyelination was attributable to increased OL progenitor cell (OPC) and mature OL numbers. At the intracellular signaling level, transition of early to late OPCs requires Erk1/2 signaling, and transition of immature to mature OLs requires mTOR signaling; thus, the PI3K/Akt/mTOR pathway plays a major role in the late stages of OL differentiation and myelination. Indeed, therapeutic treatment of EAE mice with various ERβ agonists results in increased brain-derived neurotrophic factor (BDNF) and phosphorylated (p) Akt and p-mTOR levels. It is notable that while DPN’s neuroprotective effects occur in the presence of peripheral and central inflammation, Ind-Cl is directly neuroprotective, as demonstrated by remyelination effects in the cuprizone-induced demyelination model, as well as anti-inflammatory. Elucidating the mechanisms by which ER agonists and other directly remyelinating agents modulate endogenous OPC and OL regulatory signaling is critical to the development of effective remyelinating drugs. The discovery of signaling targets to induce functional remyelination will valuably contribute to the treatment of demyelinating neurological diseases, including MS, stroke, and traumatic brain and spinal cord injury.

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mTOR: A Link from the Extracellular Milieu to Transcriptional Regulation of Oligodendrocyte Development

Cited by 62 publications

References 203 publications

The Akt/mTOR/p70S6K Pathway Is Involved in the Neuroprotective Effect of Erythropoietin on Hypoxic/Ischemic Brain Injury in a Neonatal Rat Model

The Akt/mTOR/p70S6K Pathway Is Involved in the Neuroprotective Effect of Erythropoietin on Hypoxic/Ischemic Brain Injury in a Neonatal Rat Model

Intracellular signaling pathway regulation of myelination and remyelination in the CNS

Nudging oligodendrocyte intrinsic signaling to remyelinate and repair: Estrogen receptor ligand effects

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