Integrin-Linked Kinase Regulates Process Extension in Oligodendrocytes via Control of Actin Cytoskeletal Dynamics

O’Meara, Ryan W.; Michalski, John-Paul; Anderson, Carrie L.; Bhanot, Kunal; Rippstein, Peter; Kothary, Rashmi

doi:10.1523/jneurosci.5582-12.2013

Cited by 33 publications

(45 citation statements)

References 42 publications

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“…Control of F-actin assembly is known to play an essential role in OL differentiation and initiation of myelination (O'Meara et al, 2013;Zuchero et al, 2015) but the details of the molecular network that links actin dynamics to function in OLs are not fully characterized. With this in mind, we chose to study the recently identified multifunctional actin assembly factor Jmy, which came up in our RNA-Seq screening as an mRNA that is asymmetrically distributed in OPCs during initial extension of membrane protrusions (Figure 1c (Bhat & Zhang, 1996).…”

Section: Jmy Is Expressed In Oligodendrocytes and Upregulated Durinmentioning

confidence: 99%

“…Among the most heavily regulated genes, aside from those encoding myelin proteins, are ones involved in cell cycle and motility, adhesion, and cytoskeletal remodeling. It is likely that different actin regulators have distinct roles in myelination: WASP-family verprolin-homologous protein (WAVE) and integrin-linked kinase (ILK) regulate OL differentiation and axon ensheathment (Kim et al, 2006;O'Meara et al, 2013), while the Arp2/ 3 complex, a major actin nucleator, is required for initiation of myelination in vivo (Zuchero et al, 2015), and Rho GTPases Cdc42 and Rac1 regulate myelin sheath formation (Thurnherr et al, 2006). It has been shown that myelin basic protein (MBP) triggers actin depolymerization by promoting the release of actin disassembly proteins (Zuchero et al, 2015).…”

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confidence: 99%

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Jmy regulates oligodendrocyte differentiation via modulation of actin cytoskeleton dynamics

Azevedo

Domingues

Cordelières

et al. 2018

Glia

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During central nervous system development, oligodendrocytes form structurally and functionally distinct actin-rich protrusions that contact and wrap around axons to assemble myelin sheaths. Establishment of axonal contact is a limiting step in myelination that relies on the oligodendrocyte's ability to locally coordinate cytoskeletal rearrangements with myelin production, under the control of a transcriptional differentiation program. The molecules that provide fine-tuning of actin dynamics during oligodendrocyte differentiation and axon ensheathment remain largely unidentified. We performed transcriptomics analysis of soma and protrusion fractions from rat brain oligodendrocyte progenitors and found a subcellular enrichment of mRNAs in newly-formed protrusions. Approximately 30% of protrusion-enriched transcripts encode proteins related to cytoskeleton dynamics, including the junction mediating and regulatory protein Jmy, a multifunctional regulator of actin polymerization. Here, we show that expression of Jmy is upregulated during myelination and is required for the assembly of actin filaments and protrusion formation during oligodendrocyte differentiation. Quantitative morphodynamics analysis of live oligodendrocytes showed that differentiation is driven by a stereotypical actin network-dependent "cellular shaping" program. Disruption of actin dynamics via knockdown of Jmy leads to a program fail resulting in oligodendrocytes that do not acquire an arborized morphology and are less efficient in contacting neurites and forming myelin wraps in co-cultures with neurons. Our findings provide new mechanistic insight into the relationship between cell shape dynamics and differentiation in development.

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Section: Jmy Is Expressed In Oligodendrocytes and Upregulated Durinmentioning

confidence: 99%

mentioning

confidence: 99%

Jmy regulates oligodendrocyte differentiation via modulation of actin cytoskeleton dynamics

Azevedo

Domingues

Cordelières

et al. 2018

Glia

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“…These estimates assume glucose diffusion to the middle of an internode quickly (see Figure 2); rat internodes average 240 μm (Ransom et al, 1991) while internode lengths in mouse ON average 110 μm (O'Meara et al, 2013). This internode length suggests glucose will readily diffuse; however, the predicted ATP shortfall in axons below 0.8 μm in diameter indicates a potential vulnerability of small axons.…”

Section: Energy In Axonsmentioning

confidence: 99%

Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma

Inman

Harun‐Or‐Rashid

2017

Front. Neurosci.

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Axons can be several orders of magnitude longer than neural somas, presenting logistical difficulties in cargo trafficking and structural maintenance. Keeping the axon compartment well supplied with energy also presents a considerable challenge; even seemingly subtle modifications of metabolism can result in functional deficits and degeneration. Axons require a great deal of energy, up to 70% of all energy used by a neuron, just to maintain the resting membrane potential. Axonal energy, in the form of ATP, is generated primarily through oxidative phosphorylation in the mitochondria. In addition, glial cells contribute metabolic intermediates to axons at moments of high activity or according to need. Recent evidence suggests energy disruption is an early contributor to pathology in a wide variety of neurodegenerative disorders characterized by axonopathy. However, the degree to which the energy disruption is intrinsic to the axon vs. associated glia is not clear. This paper will review the role of energy availability and utilization in axon degeneration in glaucoma, a chronic axonopathy of the retinal projection.

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“…In cell culture, loxP‐flanked genes can be excised by adding cell‐permeable Cre recombinase to the media (O'Meara et al . ). RT‐PCR showed that 50 nM Cre recombinase significantly decreased the mRNA level of Camk2b in mature OL cultures at 24 h (Fig.…”

Section: Resultsmentioning

confidence: 97%

Effects of HIV‐1 Tat on oligodendrocyte viability are mediated by CaMKIIβ–GSK3β interactions

Zou

Balinang

Paris

et al. 2019

Journal of Neurochemistry

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Myelin disruptions are frequently reported in human immunodeficiency virus (HIV)‐infected individuals and can occur in the CNS very early in the disease process. Immature oligodendrocytes (OLs) are quite sensitive to toxic increases in [Ca2+]i caused by exposure to HIV‐1 Tat (transactivator of transcription, a protein essential for HIV replication and gene expression), but sensitivity to Tat‐induced [Ca2+]i is reduced in mature OLs. Tat exposure also increased the activity of Ca2+/calmodulin‐dependent kinase IIβ (CaMKIIβ), the major isoform of CaMKII expressed by OLs, in both immature and mature OLs. Since CaMKIIβ is reported to interact with glycogen synthase kinase 3β (GSK3β), and GSK3β activity is implicated in OL apoptosis as well as HIV neuropathology, we hypothesized that disparate effects of Tat on OL viability with maturity might be because of an altered balance of CaMKIIβ–GSK3β activities. Tat expression in vivo led to increased CaMKIIβ and GSK3β activity in multiple brain regions in transgenic mice. In vitro, immature murine OLs expressed higher levels of GSK3β, but much lower levels of CaMKIIβ, than did mature OLs. Exogenous Tat up‐regulated GSK3β activity in immature, but not mature, OLs. Tat‐induced death of immature OLs was rescued by the GSK3β inhibitors valproic acid or SB415286, supporting involvement of GSK3β signaling. Pharmacologically inhibiting CaMKIIβ increased GSK3β activity in Tat‐treated OLs, and genetically knocking down CaMKIIβ promoted death in mature OL cultures treated with Tat. Together, these results suggest that the effects of Tat on OL viability are dependent on CaMKIIβ–GSK3β interactions, and that increasing CaMKIIβ activity is a potential approach for limiting OL/myelin injury with HIV infection.

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Integrin-Linked Kinase Regulates Process Extension in Oligodendrocytes via Control of Actin Cytoskeletal Dynamics

Cited by 33 publications

References 42 publications

Jmy regulates oligodendrocyte differentiation via modulation of actin cytoskeleton dynamics

Jmy regulates oligodendrocyte differentiation via modulation of actin cytoskeleton dynamics

Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma

Effects of HIV‐1 Tat on oligodendrocyte viability are mediated by CaMKIIβ–GSK3β interactions

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