CaMKII  Regulates Oligodendrocyte Maturation and CNS Myelination

Waggener, Christopher T.; Dupree, Jeffrey L.; Elgersma, Ype; Fuss, Babette

doi:10.1523/jneurosci.5875-12.2013

Cited by 49 publications

(56 citation statements)

References 45 publications

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“…To test this hypothesis, we tried to correct the spine abnormalities in L7-Cre;Itpr1 flox/flox Purkinje cells by inhibiting the CaMKIIβ/F-actin interaction. KN-93, a potent inhibitor for CaMKII, has been shown to inhibit not only kinase activity but also F-actin interaction with CaMKIIβ (35,36). Indeed, we confirmed that treatment with KN-93, but not an inactive analog KN-92, induced dissociation of HACaMKIIβ-S315A from F-actin in HeLa cells (Fig.…”

Section: Camkiiβ Phosphorylation At S315 Decreases Its F-actin Bindinsupporting

confidence: 81%

Regulation of spinogenesis in mature Purkinje cells via mGluR/PKC-mediated phosphorylation of CaMKIIβ

Sugawara

Hisatsune

Miyamoto

et al. 2017

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

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Dendritic spines of Purkinje cells form excitatory synapses with parallel fiber terminals, which are the primary sites for cerebellar synaptic plasticity. Nevertheless, how density and morphology of these spines are properly maintained in mature Purkinje cells is not well understood. Here we show an activity-dependent mechanism that represses excessive spine development in mature Purkinje cells. We found that CaMKIIβ promotes spine formation and elongation in Purkinje cells through its F-actin bundling activity. Importantly, activation of group I mGluR, but not AMPAR, triggers PKC-mediated phosphorylation of CaMKIIβ, which results in dissociation of the CaMKIIβ/ F-actin complex. Defective function of the PKC-mediated CaMKIIβ phosphorylation promotes excess F-actin bundling and leads to abnormally numerous and elongated spines in mature IP 3 R1-deficient Purkinje cells. Thus, our data suggest that phosphorylation of CaMKIIβ through the mGluR/IP 3 R1/PKC signaling pathway represses excessive spine formation and elongation in mature Purkinje cells.n the cerebellum, Purkinje cells are the sole output from the neural circuit of the cerebellar cortex, and integrate numerous synaptic inputs (1). Spines along the distal dendrites of Purkinje cells form excitatory synapses with parallel fiber terminals, which are the primary sites of cerebellar synaptic plasticity (1, 2). Spine density and morphology of Purkinje cells change significantly during development (3, 4), and morphological abnormalities of spines are closely associated with many neurological disorders (5-7). Recent studies also demonstrated that some forms of training for cerebellar motor learning results in altered spine density in Purkinje cells (8,9). Thus, maintenance of proper spine density and morphology of Purkinje cells is a critical aspect of cerebellar functions. However, the precise molecular mechanisms that maintain Purkinje cell spine density and morphology remain unclear.The actin filaments are a major structural element of the regulation of dendritic spine formation and morphology of neurons (10, 11). The actin dynamics in spines are regulated by many actinrelated molecules including Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) (12), which is one of the most abundant proteins in the brain (13). Among CaMKII isoforms (α, β, γ, and δ), CaMKIIβ possesses a specific F-actin binding domain (14) and plays an important role for regulating dendritic spine structure in hippocampal neurons. It is reported that suppression of CaMKIIβ expression leads to reduced spine formation, and conversely, overexpression of CaMKIIβ increases synapse number and motility of filopodia in hippocampal neurons (15,16). The effect of CaMKIIβ on maintaining mature spine structure requires its F-actin binding and bundling activity, but not its kinase activity (17). In addition, a recent study reported that in hippocampal neurons, activation of CaMKIIβ by postsynaptic Ca 2+ influx through the NMDA receptor and resultant autophosphorylation within the F-actin binding dom...

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Section: Camkiiβ Phosphorylation At S315 Decreases Its F-actin Bindinsupporting

confidence: 81%

Regulation of spinogenesis in mature Purkinje cells via mGluR/PKC-mediated phosphorylation of CaMKIIβ

Sugawara

Hisatsune

Miyamoto

et al. 2017

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

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“…Our recent data provided good evidence for a critical role of the calcium sensor CaMKIIβ and in particular its actin binding/stabilizing domain in regulating oligodendrocyte maturation and CNS myelination (Waggener et al 2013). Thus, CaMKIIβ and its actin binding/stabilizing domain may be directly involved in the sodium-dependent glutamate transporter-mediated effect described here.…”

Section: Resultsmentioning

confidence: 76%

“…Under experimental conditions, however, molecular mechanisms regulating cellular morphology may be uncoupled from those that regulate gene expression (Buttery and ffrench-Constant 1999; Kim et al 2006; Lafrenaye and Fuss 2011; Osterhout et al 1999; Waggener et al 2013). Thus, and to assess a potential role of L-glutamate and the activity of sodium-dependent glutamate transporters on myelin gene expression, potential changes in myelin basic protein ( Mbp ) expression were assayed using immunocytochemistry.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, signaling initiated by the activation of sodium-dependent glutamate transporters has been proposed to activate calcium/calmodulin-dependent kinase type II (CaMKII) (Flores-Mendez et al 2013; Martinez-Lozada et al 2011), and one of the four CaMKII genes, namely CaMKIIβ, has recently been implicated in the regulation of oligodendrocyte maturation and CNS myelination (Waggener et al 2013). More specifically, CaMKIIβ was implicated in promoting the morphological aspects of oligodendrocyte maturation, which are to a large extent regulated by changes in the cellular cytoskeleton (Bauer et al 2009), primarily via its actin binding/stabilizing domain rather than its well-known kinase catalytic domain.…”

Section: Introductionmentioning

confidence: 99%

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Activation of sodium‐dependent glutamate transporters regulates the morphological aspects of oligodendrocyte maturation via signaling through calcium/calmodulin‐dependent kinase IIβ's actin‐binding/‐stabilizing domain

Martínez-Lozada

Waggener

Kim

et al. 2014

Glia

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Signaling via the major excitatory amino acid glutamate has been implicated in the regulation of various aspects of the biology of oligodendrocytes, the myelinating cells of the CNS. In this respect, cells of the oligodendrocyte lineage have been described to express a variety of glutamate-responsive transmembrane proteins including sodium-dependent glutamate transporters. The latter have been well-characterized to mediate glutamate clearance from the extracellular space. However, there is increasing evidence that they also mediate glutamate-induced intracellular signaling events. Our data presented here show that activation of oligodendrocyte expressed sodium-dependent glutamate transporters, in particular GLT-1 and GLAST, promotes the morphological aspects of oligodendrocyte maturation. This effect was found to be associated with a transient increase in intracellular calcium levels and a transient phosphorylation event at the serine (S)371 site of the calcium sensor calcium/calmodulin-dependent kinase IIβ (CaMKIIβ). The potential regulatory S371 site is located within CaMKIIβ’s previously defined actin binding/stabilizing domain, and phosphorylation events within this domain were identified in our studies as a requirement for sodium-dependent glutamate transporter-mediated promotion of oligodendrocyte maturation. Furthermore, our data provide good evidence for a role of these phosphorylation events in mediating detachment of CaMKIIβ from filamentous (F)-actin, thereby allowing a remodeling of the oligodendrocyte’s actin cytoskeleton. Taken together with our recent findings, which demonstrated a crucial role of CaMKIIβ in regulating CNS myelination in vivo, our data strongly suggest that a sodium-dependent glutamate transporter-CaMKIIβ-actin cytoskeleton axis plays an important role in the regulation of oligodendrocyte maturation and CNS myelination.

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“…PLCs participate in phosphatidylinositol 4,5-bisphosphate (PIP 2 ) metabolism and lipid signaling pathways in a calciumdependent manner, and are essential for intracellular calcium homeostasis (53). CaMK is a serine/threonine-specific protein kinase regulated by the Ca 2+ /calmodulin complex that has been shown to regulate oligodendrocyte maturation and myelination (54). Strikingly, nine of the 15 members of the PLC family and six CaMKs were up-regulated in oligodendrocytes in SOD1 G37R mice at this early symptomatic stage (Fig.…”

Section: Gene Expression Changes In Oligodendrocytes At An Early Sympmentioning

confidence: 99%

Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS

Sun

Ling

et al. 2015

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

165

152

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Ubiquitous expression of amyotrophic lateral sclerosis (ALS)-causing mutations in superoxide dismutase 1 (SOD1) provokes noncell autonomous paralytic disease. By combining ribosome affinity purification and high-throughput sequencing, a cascade of mutant SOD1-dependent, cell type-specific changes are now identified. Initial mutant-dependent damage is restricted to motor neurons and includes synapse and metabolic abnormalities, endoplasmic reticulum (ER) stress, and selective activation of the PRKR-like ER kinase (PERK) arm of the unfolded protein response. PERK activation correlates with what we identify as a naturally low level of ER chaperones in motor neurons. Early changes in astrocytes occur in genes that are involved in inflammation and metabolism and are targets of the peroxisome proliferator-activated receptor and liver X receptor transcription factors. Dysregulation of myelination and lipid signaling pathways and activation of ETS transcription factors occur in oligodendrocytes only after disease initiation. Thus, pathogenesis involves a temporal cascade of cell type-selective damage initiating in motor neurons, with subsequent damage within glia driving disease propagation.

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CaMKII Regulates Oligodendrocyte Maturation and CNS Myelination

Cited by 49 publications

References 45 publications

Regulation of spinogenesis in mature Purkinje cells via mGluR/PKC-mediated phosphorylation of CaMKIIβ

Regulation of spinogenesis in mature Purkinje cells via mGluR/PKC-mediated phosphorylation of CaMKIIβ

Activation of sodium‐dependent glutamate transporters regulates the morphological aspects of oligodendrocyte maturation via signaling through calcium/calmodulin‐dependent kinase IIβ's actin‐binding/‐stabilizing domain

Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS

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