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Title: Zebrafish : a transparent screening model of myelination
Author: Buckley, C. E.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2010
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This thesis provides a description of the temporal dynamics of myelination in zebrafish larvae, demonstrating that oligodendrocytes are present in zebrafish larvae from ld.p.f. and myelination commences by 3d.p.f. The regulation of myelination is dependent on the growth of axons and not on their absolute size. Zebrafish larvae proved an accessible myelination model. A medium throughput in vivo reprofiling screen was consequently set up for pro-myelination compounds. Changes in oligodendrocyte lineage cell number in response to different compound treatments were assessed using the olig2:EGFP transgenic line of zebrafish larvae. As well as patentable compounds such as isoxicam, unknown for its effect on myelination, several compounds were identified that were known to affect oligodendrocyte differentiation and/or myelination, such as the sex steroid precursor, pregnenolone and the PPAR agonist, bezafibrate. The identification of these compounds therefore validated the screening techniques used. Analysis of mbp mRNA transcript levels by qPCR identified 3 compounds that decreased transcript levels, one of which was PP2. The effect of PP2 was specific to src kinase inhibition, confirming the importance of this known pathway in regulating myelination and again validating the screen. However, it was not possible to increase mbp levels with any of the compounds screened and there was no apparent correlation between the number of olig2+ cells and mbp transcript levels. Preliminary further analysis of some of the compounds identified in the olig2+ cell counting screen, such as isoxicam, also illustrated that the effects on olig2+ cell number were not always specific to oligodendrocytes. Compounds with potential pro-myelination effects should now be analysed further for their specificity of effect, both in zebrafish models of myelination and in remyelination models.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available