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Title: Axon-glia interactions during central nervous system myelination
Author: Almeida, Rafael
ISNI:       0000 0004 6062 7921
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2015
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Myelination drastically speeds up action potential propagation along axons, which is fundamental for the correct function of neuronal circuits. However, axon-oligodendrocyte interactions regulating the onset of myelin formation remain unclear. I sought to determine how reticulospinal axons control myelination, as they are the first myelinated in the zebrafish spinal cord. I genetically manipulated zebrafish in order to either remove such axons from a region of the spinal cord, or to increase their number, and characterized oligodendrocyte-lineage cells following this axonal loss- or gain-of-function. In kinesin-binding protein (kbp) mutants, reticulospinal hindbrain neurons start axonogenesis but axons fail to grow along the entire spinal cord as in wildtype, providing an axon-deficient posterior spinal cord and an intact anterior region. I found that early stages of oligodendrocyte development, such as the specification of oligodendrocyte precursors, their distribution and migration were not affected in the posterior spinal cord of these mutants. However, both the proliferation and the survival of late precursors were impaired, resulting in a significant reduction of mature oligodendrocytes in the posterior region of mutants at the onset of myelination. Since the anterior spinal cord of mutants is indistinguishable from wildtype, these results demonstrate that reticulospinal axons provide a mitogenic and a survival signal to a subset of developing OPCs, enabling their differentiation and lineage progression. I then found that the absence of reticulospinal axons did not affect the timing of oligodendrocyte differentiation, which matured on time, suggesting that this follows an intrinsic timer, as previous studies suggested. Oligodendrocytes also did not myelinate incorrect axonal targets, but instead adapted to the reduced axonal surface by elaborating fewer myelin sheaths. Additionally, oligodendrocytes made shorter sheaths, and also incorrectly ensheathed neuron somas in the mutant spinal cord, suggesting that either kbp function or a precise amount of axonal surface are required to prevent ectopic myelination of somas and to promote the longitudinal growth of myelin sheaths. In wildtype animals, the two reticulospinal Mauthner axons are the very first myelinated in the spinal cord. In animals where Notch1a function is temporarily abrogated or hoxb1 genes are temporarily upregulated, supernumerary Mauthner neurons are generated. I found that these extra axons are robustly myelinated, with no impairment of myelination of adjacent axons. Surprisingly, the number of oligodendrocytes was not altered, but I found that each individual oligodendrocyte elaborated more myelin sheaths, whose total length was also longer than in wildtypes. Additionally, dorsal oligodendrocytes, which normally myelinate only small-calibre dorsal axons, readily extended processes ventrally to myelinate the supernumerary large-calibre Mauthner axons, in addition to small-calibre axons. These results suggest that oligodendrocytes are plastic and are not destined to myelinate a particular type of axon, and conversely, that axonal signals that induce myelination are similar for different axons. The long-standing observation that oligodendrocytes tend to myelinate either few large axons or many small axons thus reflects local interactions of oligodendrocyte processes with the nearby axons, rather than different subtypes of oligodendrocytes specified by an intrinsic programme of differentiation. Collectively, this work shows that axons extensively influence both oligodendrocyte lineage progression and oligodendrocyte myelinating potential in vivo.
Supervisor: Lyons, David ; Brophy, Peter Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: myelin ; zebrafish ; oligodendrocyte