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Title: Investigating the mechanisms directing oligodendrocyte precursor cell (OPC) development in the zebrafish hindbrain
Author: Boyd, Penelope
ISNI:       0000 0004 5363 498X
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2014
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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.
Supervisor: Wood, Jonathon Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available