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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    • "Zebrafish were maintained and bred as described (Westerfield, 1993) and all procedures approved by the University of Utah Institutional Animal Care and Use Committee (IACUC#15- 10011). The Tg(sox10:mRFP) transgenic line was described previously (Kirby et al., 2006). The 3042bp proximal snai1b promoter immediately adjacent to the start ATG codon was amplified Disease Models & Mechanisms @BULLET DMM @BULLET Advance article by standard PCR with primers containing BamH1 (5') and EcoR1 (3') restriction enzyme sites. "
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    ABSTRACT: The epithelial to mesenchymal transition (EMT) is a highly conserved morphogenetic program essential for embryogenesis, regeneration and cancer metastasis. In cancer cells, EMT also triggers cellular reprogramming and chemoresistance, which underlie disease relapse and decreased survival. Hence, identifying compounds that block EMT is essential to prevent or eradicate disseminated tumor cells. Here, we establish a whole animal-based EMT reporter in zebrafish for rapid drug screening called Tg(snai1b:GFP), which labels epithelial cells undergoing EMT to produce sox10-positive neural crest (NC) cells. Time-lapse and lineage analysis of Tg(snai1b:GFP) embryos reveal that cranial NC cells delaminate from two regions; an early population delaminates adjacent to the neural plate while a later population delaminates from within the dorsal neural tube. Treating Tg(snai1b:GFP) embryos with candidate small molecule EMT compounds identified TP-0903, a multi-kinase inhibitor that blocked cranial NC delamination in both the lateral and medial populations. RNA-Seq analysis and chemical rescue experiments show TP-0903 acts through stimulating retinoic acid (RA) biosynthesis and RA-dependent transcription. These studies identify TP-0903 as a new therapeutic for activating RA in vivo and raise the possibility that RA-dependent inhibition of EMT may contribute to its prior success in eliminating disseminated cancer cells.
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    • "The TeNT transgenic fish described above provide an excellent opportunity to examine this question. Earlier studies using the sox10:RFP reporter line (Kirby et al., 2006) demonstrated that OPC exhibit highly motile processes during the time-frame spanning OPC specification to the initiation of axon wrapping (approximately 36e72 h post fertilization (hpf)). The study by Hines et al. (2015) "
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    ABSTRACT: The formation and repair of myelin involves alterations in the molecular and physical properties of oligodendrocytes, and highly coordinated interactions with their target axons. Characterising the nature and timing of these events at the molecular and cellular levels illuminates the fundamental events underlying myelin formation, and provides opportunities for the development of therapies to replace myelin lost through traumatic injury and inflammation. The dynamic nature of these events requires that live-imaging methods be used to capture this information accurately and completely. Developments in imaging technologies, and model systems suitable for their application to myelination, have advanced the study of myelin formation, injury and repair. Similarly, new techniques for single molecule imaging, and novel imaging probes, are providing opportunities to resolve the dynamics of myelin proteins during myelination. Here, we explore these developments in the context of myelin formation and injury, identify unmet needs within the field where progress can be advanced through live-imaging approaches, identify technical challenges that are limiting this progress, and highlight practical applications for these approaches that could lead to therapies for the protection of oligodendrocytes and myelin from injury, and restore myelin lost through injury and disease.
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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.
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