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Investigating the mechanisms directing oligodendrocyte precursor cell (OPC) development in the zebrafish hindbrain

boyd, Penelope (2014) Investigating the mechanisms directing oligodendrocyte precursor cell (OPC) development in the zebrafish hindbrain. PhD thesis, University of Sheffield.

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Abstract

Oligodendrocytes are the myelinating cells of the central nervous system (CNS) and are implicated in the pathobiology of many CNS diseases including multiple sclerosis and schizophrenia. Oligodendrocyte precursor cells (OPCs) are capable of migrating long distances, but the mechanisms governing the migration of OPCs to their axonal destinations are not fully understood. We sought to understand the extrinsic and intrinsic factors that contribute to the migration of a subset of OPCs in the zebrafish hindbrain. We utilized the zebrafish transgenic tg(olig2:gfp) line to mark OPCs and characterise their normal migration patterns. These cells normally first migrate in a ventral direction, after which they migrate away from the midline dorsolaterally to populate the hindbrain. However, how these cells initiate migration in a ventral direction is not known. We have found that removing Hedgehog signalling at the onset of their migratory phase results in a failure of OPCs to migrate in their normal ventral fashion, while increasing Hedgehog signalling results in hypermigration of these cells. This suggests that Hedgehog might not just be important for OPC fate specification, via induction of transcription factors such as olig2, but may also be actively involved in the development of these cells post-specification. We propose that Sonic Hedgehog acts as a chemoattractant to drive the initial ventral migration of hindbrain OPCs and furthermore provide evidence that it may function at least in part by inducing disc1, a schizophrenia risk factor gene, which has known roles in neural crest and neuronal migration. With several studies supporting a role of DISC1 in neuronal migration it has been hypothesised that DISC1 could also play a role in the process of myelination. White matter abnormalities are consistently reported in schizophrenia patients, and it is hypothesised that OPC migratory defects may cause these documented white matter abnormalities due to early genetic dysfunction. This thesis has provided evidence for a link between a well characterised schizophrenia risk factor gene, early OPC migration events and a fundamental signalling pathway.

Item Type: Thesis (PhD)
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield)
The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)
Identification Number/EthosID: uk.bl.ethos.638964
Depositing User: Miss Penelope boyd
Date Deposited: 13 Mar 2015 13:13
Last Modified: 12 Oct 2018 09:22
URI: http://etheses.whiterose.ac.uk/id/eprint/8372

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