Kirby, B.B. et al. In vivo time-lapse imaging shows dynamic oligodendrocyte progenitor behavior during zebrafish development. Nat. Neurosci. 9, 1506-1511

Department of Biological Sciences, Vanderbilt University, 465 21st Avenue South, Nashville, Tennessee 37232, USA.
Nature Neuroscience (Impact Factor: 16.1). 01/2007; 9(12):1506-11. DOI: 10.1038/nn1803
Source: PubMed


Myelinating oligodendrocytes arise from migratory and proliferative oligodendrocyte progenitor cells (OPCs). Complete myelination requires that oligodendrocytes be uniformly distributed and form numerous, periodically spaced membrane sheaths along the entire length of target axons. Mechanisms that determine spacing of oligodendrocytes and their myelinating processes are not known. Using in vivo time-lapse confocal microscopy, we show that zebrafish OPCs continuously extend and retract numerous filopodium-like processes as they migrate and settle into their final positions. Process remodeling and migration paths are highly variable and seem to be influenced by contact with neighboring OPCs. After laser ablation of oligodendrocyte-lineage cells, nearby OPCs divide more frequently, orient processes toward the ablated cells and migrate to fill the unoccupied space. Thus, process activity before axon wrapping might serve as a surveillance mechanism by which OPCs determine the presence or absence of nearby oligodendrocyte-lineage cells, facilitating uniform spacing of oligodendrocytes and complete myelination.

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    • "Second, only axons above a certain diameter are myelinated (Waxman and Bennett, 1972), and third, recent data suggest that internodes are not evenly spaced throughout the length of the axon (Tomassy et al., 2014). Live imaging in zebrafish has shown that oligodendrocytes go through a dynamic period of process extensions and retractions prior to the final selection of the axons to be myelinated (Kirby et al., 2006). However, following the initial wrapping of the oligodendrocyte processes around the axon, very few retractions are observed (Czopka et al., 2013), suggesting the existence of a narrow time window in which the axons are selected. "
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    ABSTRACT: In the central nervous system, myelination of axons is required to ensure fast saltatory conduction and for survival of neurons. However, not all axons are myelinated, and the molecular mechanisms involved in guiding the oligodendrocyte processes toward the axons to be myelinated are not well understood. Only a few negative or positive guidance clues that are involved in regulating axo-glia interaction prior to myelination have been identified. One example is laminin, known to be required for early axo-glia interaction, which functions through α6β1 integrin. Here, we identify the Eph-ephrin family of guidance receptors as novel regulators of the initial axo-glia interaction, preceding myelination. We demonstrate that so-called forward and reverse signaling, mediated by members of both Eph and ephrin subfamilies, has distinct and opposing effects on processes extension and myelin sheet formation. EphA forward signaling inhibits oligodendrocyte process extension and myelin sheet formation, and blocking of bidirectional signaling through this receptor enhances myelination. Similarly, EphB forward signaling also reduces myelin membrane formation, but in contrast to EphA forward signaling, this occurs in an integrin-dependent manner, which can be reversed by overexpression of a constitutive active β1-integrin. Furthermore, ephrin-B reverse signaling induced by EphA4 or EphB1 enhances myelin sheet formation. Combined, this suggests that the Eph-ephrin receptors are important mediators of bidirectional signaling between axons and oligodendrocytes. It further implies that balancing Eph-ephrin forward and reverse signaling is important in the selection process of axons to be myelinated.
    ASN Neuro 09/2015; 7(5). DOI:10.1177/1759091415602859 · 4.02 Impact Factor
    • "Key transcription factors known from mammalian studies, such as Nkx2.2, Sox10, and Olig1, have all been reported to function in oligodendrocyte differentiation in zebrafish as well (Kirby et al., 2006; Kucenas et al., 2008; Li et al., 2007; Schebesta and Serluca, 2009), meaning that patterns and general principles of myelination are conserved between fish and mammals. The function of numerous other molecules on oligodendrocyte development have been studied in zebrafish and some of them have recently been reviewed by Preston and Macklin in great detail (Preston and Macklin, 2015). "
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    ABSTRACT: Myelin is the multi-layered membrane that surrounds most axons and is produced by oligodendrocytes in the central nervous system (CNS). In addition to its important role in enabling rapid nerve conduction, it has become clear in recent years that myelin plays additional vital roles in CNS function. Myelinating oligodendrocytes provide metabolic support to axons and active myelination is even involved in regulating forms of learning and memory formation. However, there are still large gaps in our understanding of how myelination by oligodendrocytes is regulated. The small tropical zebrafish has become an increasingly popular model organism to investigate many aspects of nervous system formation, function, and regeneration. This is mainly due to two approaches for which the zebrafish is an ideally suited vertebrate model-(1) in vivo live cell imaging using vital dyes and genetically encoded reporters, and (2) gene and target discovery using unbiased screens. This review summarizes how the use of zebrafish has helped understand mechanisms of oligodendrocyte behavior and myelination in vivo and discusses the potential use of zebrafish to shed light on important future questions relating to myelination in the context of CNS development, function and repair. GLIA 2015. © 2015 Wiley Periodicals, Inc.
    Glia 08/2015; DOI:10.1002/glia.22897 · 6.03 Impact Factor
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    • "To analyze the initial stages of CNS myelination, we utilized the Tg(nkx2.2a:meGFP) animal line, which expresses a membrane-tethered EGFP in a subset of oligodendrocyte precursor cells, pre-myelinating oligodendrocytes , and early myelinating oligodendrocytes (Kirby et al., 2006). F-actin distribution and dynamics were resolved by co-expressing Lifeact (here fused with the red fluorescent protein tag-RFPt under control of sox10 upstream regulatory sequences), which binds to F-actin and allows imaging for several hours without interfering with actin polymerization dynamics (Riedl et al., 2010). "
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    ABSTRACT: During CNS development, oligodendrocytes wrap their plasma membrane around axons to generate multilamellar myelin sheaths. To drive growth at the leading edge of myelin at the interface with the axon, mechanical forces are necessary, but the underlying mechanisms are not known. Using an interdisciplinary approach that combines morphological, genetic, and biophysical analyses, we identified a key role for actin filament network turnover in myelin growth. At the onset of myelin biogenesis, F-actin is redistributed to the leading edge, where its polymerization-based forces push out non-adhesive and motile protrusions. F-actin disassembly converts protrusions into sheets by reducing surface tension and in turn inducing membrane spreading and adhesion. We identified the actin depolymerizing factor ADF/cofilin1, which mediates high F-actin turnover rates, as an essential factor in this process. We propose that F-actin turnover is the driving force in myelin wrapping by regulating repetitive cycles of leading edge protrusion and spreading. Copyright © 2015 Elsevier Inc. All rights reserved.
    Developmental Cell 07/2015; 34(2). DOI:10.1016/j.devcel.2015.05.013 · 9.71 Impact Factor
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