ZFP191 is required by oligodendrocytes for CNS myelination

Howng, Shen Yi B.; Avila, Robin; Emery, Ben; Τράκα, Μαρία; Lin, Wensheng; Watkins, Trent A.; Cook, Susan A.; Bronson, Roderick T.; Davisson, Muriel T.; Barres, Ben A.; Popko, Brian

doi:10.1101/gad.1864510

Cited by 74 publications

(68 citation statements)

References 46 publications

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“…SIN-1 or peroxynitrite induced PKC activation may occur simultaneously with zinc liberation from PKC, or is caused by zinc released from mitochondria and the other zinc binding proteins, such as metallothioneins and zinc finger proteins (Hao and Maret, 2005;Maret, 2008;Zhang et al, 2007). Recently, an elegant study has demonstrated that mutations in a zinc finger protein ZFP191 can disrupt the myelinating function of differentiated OLs (Howng et al, 2010). We speculate that the release of zinc from ZFP191 may inhibit its function and reduce the expression of an array of myelin-related genes.…”

Section: Discussionmentioning

confidence: 99%

Protein kinase C mediates peroxynitrite toxicity to oligodendrocytes

Lin

Tchantchou

et al. 2011

Molecular and Cellular Neuroscience

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Peroxynitrite has been suggested to be the potent oxidant causing toxicity to neurons and oligodendrocytes (OLs). Our previous studies have illustrated that intracellular zinc liberation contributes to peroxynitrite toxicity to mature OLs. In this study, we further investigated the signaling pathways involved in this event and identified protein kinase C (PKC) as an important early signaling molecule. We found that a non-selective PKC inhibitor bisindolylmaleimide-1 blocked OL toxicity induced by a peroxynitrite generator SIN-1 and exogenous zinc. The protective effects were due to its inhibition on ERK1/2 phosphorylation and ROS generation. The same phenomenon was also observed in OLs following prolonged treatment with phorbol 12 myristate 13 acetate (PMA), which downregulates the conventional and the novel PKC isoforms (cPKCs and nPKCs). To determine the role of specific PKC isoforms, we found that a specific nPKC inhibitor rottlerin significantly reduced SIN-1-or zinc-induced toxicity, whereas Go6976, a cPKC inhibitor, reduced OL toxicity triggered by zinc, but not by SIN-1 at high concentrations. Rottlerin was more potent than Go6976 to attenuate ERK1/2 phosphorylation and ROS generation induced by SIN-1 or zinc. Surprisingly, zinc only induced phosphorylation of PKCθ, but not PKCδ. Knockdown of PKCθ using lentiviral shRNA attenuated SIN-1-or zinc-induced toxicity. These results suggest that PKCθ might be the major PKC isoform involved in peroxynitrite and zinc toxicity to mature OLs, and provide a rationale for development of specific inhibitors of PKCθ in the treatment of multiple sclerosis and other neurodegenerative diseases, in which peroxynitrite formation plays a pathogenic role.Published by Elsevier Inc.

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Section: Discussionmentioning

confidence: 99%

Protein kinase C mediates peroxynitrite toxicity to oligodendrocytes

Lin

Tchantchou

et al. 2011

Molecular and Cellular Neuroscience

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“…Myelin gene regulatory factor (MRF) (Emery et al 2009), the zinc finger protein 191 (Zfp191) (Howng et al 2010), and the TF Ying Yang 1 (YY1) (He et al 2007) are all thought to function after cell cycle exit and terminal differentiation. Mice lacking MRF in the oligodendroglial lineage continue to generate OLs; however, these cells do not fully mature and display defects in myelin gene expression and myelin internode formation (Emery et al 2009).…”

Section: Regulation Of Developmental Myelinationmentioning

confidence: 99%

Myelin Regeneration: A Recapitulation of Development?

Fancy

Chan

Baranzini

et al. 2011

Annu. Rev. Neurosci.

298

231

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The developmental process of myelination and the adult regenerative process of remyelination share the common objective of investing nerve axons with myelin sheaths. A central question in myelin biology is the extent to which the mechanisms of these two processes are conserved, a concept encapsulated in the recapitulation hypothesis of remyelination. This question also has relevance for translating myelin biology into a better understanding of and eventual treatments for human myelin disorders. Here we review the current evidence for the recapitulation hypothesis and discuss recent findings in the development and regeneration of myelin in the context of human neurological disease.

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“…For example, microRNAs, in particular, miRNA-219 and miRNA-338, actively repress the activity of crit-ical transcription factors and signaling pathways, such as Sox5/6, Hes5, and PDGFRa (Dugas et al 2010; Zhao et al 2010;Hudish et al 2013). At the same time that the activity of other transcription factors, including repressors of repressors and activators of transcription, like myogenic regulatory factors (MRFs), Nxk2.2, Olig1, Sox10, YY1, and Zfp191, are turned on (He et al 2007;Wegner 2008;Emery et al 2009;Howng et al 2010;Meijer et al 2012;Bujalka et al 2013). Once myelination has started, the PtdIns(3,4,5)P3/Akt/mTor and ERK1/2-dependent signaling pathways are essential in driving myelin formation forward until fully matured sheaths with optimal g-ratios have been generated (Flores et al 2008;Tyler et al 2009;Goebbels et al 2010;Ishii et al 2013).…”

Section: Myelin Assemblymentioning

confidence: 99%

Oligodendrocytes: Myelination and Axonal Support

Simons

Nave

2015

Cold Spring Harb Perspect Biol

615

463

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Myelinated nerve fibers have evolved to enable fast and efficient transduction of electrical signals in the nervous system. To act as an electric insulator, the myelin sheath is formed as a multilamellar membrane structure by the spiral wrapping and subsequent compaction of the oligodendroglial plasma membrane around central nervous system (CNS) axons. Current evidence indicates that the myelin sheath is more than an inert insulating membrane structure. Oligodendrocytes are metabolically active and functionally connected to the subjacent axon via cytoplasmic-rich myelinic channels for movement of macromolecules to and from the internodal periaxonal space under the myelin sheath. This review summarizes our current understanding of how myelin is generated and also the role of oligodendrocytes in supporting the long-term integrity of myelinated axons. When Virchow analyzed the fine structure of the brain in the 1850s, he recognized that there were more cells within the "Nervenkitt" than astrocytes, but because of the imperfect staining methods, they remained obscure and were only named the "third element" (reviewed in Somjen 1988; Rosenbluth 1999). It was decades later that Pío del Río-Hortega (1921) applied a staining method involving silver carbonate, thereby shedding new light on the rest of the interstitial cells. These cells were found to contain numerous short processes and were named oligodendroglia and microglia. Defining features of oligodendrocytes were their small cell bodies filled with nuclei containing large amounts of chromatin, and their cellular extensions that lacked fibers but were filled with cytoplasmic granules (Fig. 1). When the tissue was optimally preserved, the silver impregnation uncovered a tremendous complexity of extensions (Fig. 1). del Río-Hortega was able to distinguish four types of oligodendrocytes ( Fig. 1): Type I cells generate many different myelin segments on small diameter axons in diverse orientations; type II cells are similar to type I in size and number, but myelin segments run in parallel to each other; type III oligodendrocytes ensheath fewer axons of larger diameter; and type IV oligodendrocytes have a cell body closely apposed to a single very large axon similar to Schwann cells. From the staining, it became clear that some of the processes run in parallel to axons and appeared to cover the axons with "myelin," a term that was introduced by Virchow already in

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ZFP191 is required by oligodendrocytes for CNS myelination

Cited by 74 publications

References 46 publications

Protein kinase C mediates peroxynitrite toxicity to oligodendrocytes

Protein kinase C mediates peroxynitrite toxicity to oligodendrocytes

Myelin Regeneration: A Recapitulation of Development?

Oligodendrocytes: Myelination and Axonal Support

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