Lithium chloride stimulates PLP and MBP expression in oligodendrocytes via Wnt/β-catenin and Akt/CREB pathways

Meffre, Delphine; Massaad, Charbel; Grenier, Julien

doi:10.1016/j.neuroscience.2014.10.064

Cited by 68 publications

(46 citation statements)

References 45 publications

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“…The blockage of c-Jun expression by lithium has been documented previously [57,58] and may explain the antagonistic action on SC proliferation [59]. However, our studies differ from existing literature reporting induction of myelin gene expression in response to lithium in SCs [25,22] and oligodendrocytes [60,43]. The study by Ogata et al [25] reported that co-stimulation of postnatal rat SCs with LiCl (16 mM) and Fsk increased the levels of MAG mRNA.…”

Section: Discussioncontrasting

confidence: 49%

Lithium Reversibly Inhibits Schwann Cell Proliferation and Differentiation Without Inducing Myelin Loss

et al. 2016

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This study was undertaken to examine the bioactivity, specificity and reversibility of lithium’s action on the growth, survival, proliferation and differentiation of cultured Schwann cells (SCs). In isolated SCs, lithium promoted a state of cell cycle arrest that featured extensive cell enlargement and c-Jun downregulation in the absence of increased expression of myelin-associated markers. In addition, lithium effectively prevented mitogen-induced S-phase entry without impairing cell viability. When lithium was administered together with differentiating concentrations of cAMP analogs, a dramatic inhibition of the expression of the master regulator of myelination Krox-20 was observed. Likewise, lithium antagonized the cAMP-dependent expression of various myelin markers such as protein zero, periaxin and galactocerebroside and allowed SCs to maintain high levels of expression of immature SC markers even in the presence of high levels of cAMP and low levels of c-Jun. Most importantly, the inhibitory action of lithium on SC proliferation and differentiation was shown to be dose dependent, specific and reversible upon removal of lithium compounds. In SC-neuron cultures, lithium suppressed myelin sheath formation while preserving axonal integrity, SC-axon contact and basal lamina formation. Lithium was unique in its ability to prevent the onset of myelination without promoting myelin degradation or SC dedifferentiation. To conclude, our results underscored an unexpected antagonistic action of lithium on SC mitogenesis and myelin gene expression. We suggest that lithium represents an attractive pharmacological agent to safely and reversibly suppress the onset of SC proliferation, differentiation and myelination while maintaining the integrity of pre-existing myelinated fibers.

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Section: Discussioncontrasting

confidence: 49%

Lithium Reversibly Inhibits Schwann Cell Proliferation and Differentiation Without Inducing Myelin Loss

et al. 2016

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“…Treatments that induce a sustained elevation of cAMP levels in oligodendrocytes activate CREB and subsequently increase MBP protein levels by activating the MBP promoter (24,26,27,44). Conversely, inactivation of CREB has been reported in the presence of inhibitors of oligodendrocyte maturation, such as GSK3␤ (45) or CNS myelin (12).…”

Section: Discussionmentioning

confidence: 99%

The Orphan G Protein-coupled Receptor GPR17 Negatively Regulates Oligodendrocyte Differentiation via Gαi/o and Its Downstream Effector Molecules

Simon

Hennen

Merten

et al. 2016

Journal of Biological Chemistry

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Recent studies have recognized G protein-coupled receptors as important regulators of oligodendrocyte development. GPR17, in particular, is an orphan G protein-coupled receptor that has been identified as oligodendroglial maturation inhibitor because its stimulation arrests primary mouse oligodendrocytes at a less differentiated stage. However, the intracellular signaling effectors transducing its activation remain poorly understood. Here, we use Oli-neu cells, an immortalized cell line derived from primary murine oligodendrocytes, and primary rat oligodendrocyte cultures as model systems to identify molecular targets that link cell surface GPR17 to oligodendrocyte maturation blockade. We demonstrate that stimulation of GPR17 by the small molecule agonist MDL29,951 (2-carboxy-4,6-dichloro-1H-indole-3-propionic acid) decreases myelin basic protein expression levels mainly by triggering the G␣ i/o signaling pathway, which in turn leads to reduced activity of the downstream cascade adenylyl cyclase-cAMP-PKA-cAMP response element-binding protein (CREB). In addition, we show that GPR17 activation also diminishes myelin basic protein abundance by lessening stimulation of the exchange protein directly activated by cAMP (EPAC), thus uncovering a previously unrecognized role for EPAC to regulate oligodendrocyte differentiation. Together, our data establish PKA and EPAC as key downstream effectors of GPR17 that inhibit oligodendrocyte maturation. We envisage that treatments augmenting PKA and/or EPAC activity represent a beneficial approach for therapeutic enhancement of remyelination in those demyelinating diseases where GPR17 is highly expressed, such as multiple sclerosis.Myelination is a central nervous system (CNS) process where oligodendrocytes establish myelin sheaths that stabilize, protect, and electrically insulate neuronal axons. During postnatal development, oligodendrocytes progress through a sequence of differentiation steps from oligodendrocyte precursor cells (OPCs) 5 to myelinating mature oligodendrocytes (1). Failure during this process leads to impaired myelination and, consequently, to slow conduction of signals along nerves, which results in debilitating symptoms such as paralysis and cognitive impairments. Likewise, in many severe neurological disorders, among others multiple sclerosis (MS), loss of oligodendrocytes and destruction of CNS myelin precedes the serious neurological deficits. Although OPCs are abundant in chronic MS lesion sites, no remyelination occurs, which suggests that oligodendrocyte differentiation does not take place due to either the absence of pro-myelinating signals or presence of myelination inhibitors in the MS lesion (2, 3).During the previous years, an increasing number of oligodendroglial differentiation inhibitors have been identified (for review see Ref. 4). Genetic evidence from transgenic mice supports the notion that the orphan G protein-coupled receptor GPR17 (5) negatively regulates oligodendrocyte maturation and myelination (6). Notably, GPR17 is highly abundant...

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“…An unexpected, positive regulatory function in OPC formation as well as maturation was recently demonstrated in vivo by genetic ablation (Dai et al, 2014). Lithium chloride, which activates beta-catenin and which is already being used to treat neurological disease such as bipolar mood disorder (Chuang, 2004, 2005) based on its anti-apoptotic effects (Beural and Jope, 2006), was recently found to promote the expression of myelin genes in OLs in culture (Meffre et al, 2015). It should be noted that the effects of LiCl and beta-catenin (Meffre et al, 2014) on terminal OL differentiation are not identical, because of the specific involvement of Akt/CREB activation with lithium that overcomes the inhibitory effect of Wnt on terminal OPC differentiation (Azim and Butt, 2011).…”

Section: Strategies For Improving Protection and Repairmentioning

confidence: 99%

Pharmacological approaches to intervention in hypomyelinating and demyelinating white matter pathology

Chew

DeBoy

2016

Neuropharmacology

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White matter disease afflicts both developing and mature central nervous systems. Both cell intrinsic and extrinsic dysregulation result in profound changes in cell survival, axonal metabolism and functional performance. Experimental models of developmental white matter (WM) injury and demyelination have not only delineated mechanisms of signaling and inflammation, but have also paved the way for the discovery of pharmacological approaches to intervention. These reagents have been shown to enhance protection of the mature oligodendrocyte cell, accelerate progenitor cell recruitment and/or differentiation, or attenuate pathological stimuli arising from the inflammatory response to injury. Here we highlight reports of studies in the CNS in which compounds, namely peptides, hormones, and small molecule agonists/antagonists, have been used in experimental animal models of demyelination and neonatal brain injury that affect aspects of excitotoxicity, oligodendrocyte development and survival, and progenitor cell function, and which have been demonstrated to attenuate damage and improve WM protection in experimental models of injury. The molecular targets of these agents include growth factor and neurotransmitter receptors, morphogens and their signaling components, nuclear receptors, as well as the processes of iron transport and actin binding. By surveying the current evidence in non-immune targets of both the immature and mature WM, we aim to better understand pharmacological approaches modulating endogenous oligodendroglia that show potential for success in the contexts of developmental and adult WM pathology.

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Lithium chloride stimulates PLP and MBP expression in oligodendrocytes via Wnt/β-catenin and Akt/CREB pathways

Cited by 68 publications

References 45 publications

Lithium Reversibly Inhibits Schwann Cell Proliferation and Differentiation Without Inducing Myelin Loss

Lithium Reversibly Inhibits Schwann Cell Proliferation and Differentiation Without Inducing Myelin Loss

The Orphan G Protein-coupled Receptor GPR17 Negatively Regulates Oligodendrocyte Differentiation via Gαi/o and Its Downstream Effector Molecules

Pharmacological approaches to intervention in hypomyelinating and demyelinating white matter pathology

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