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Title: Genetic mechanisms regulating neural stem cell self-renewal and differentiation in the central nervous system of Drosophila
Author: Kim, Dongwook
ISNI:       0000 0004 5368 1698
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2014
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Asymmetric cell division plays a fundamental role in maintaining a balance between stem cell self-renewal and differentiation. A failure of this balance results in over-proliferation of stem cells, which could eventually lead to neoplastic over-growth and mestasis, i.e. tumourigenesis. Key components of this genetic machinery in Drosophila CNS involves unequal segregation of differentiation factors such as brain tumour (Brat) and prospero (Pros), with their adaptor protein miranda (Mira). Using post-embryonic neuroblasts (NBs) as a model, I demonstrate basal co-localisation of Mira/Brat/Pros during late metaphase. RNAi-mediated knockdown of Brat or Pros result in excess stem cell self-renewal at the expense of neuronal differentiation, leading to over-proliferation of NBs These data suggest Mira/Brat/Pros are likely to form a complex during post-embryonic NB division. However, how these cell fate determinants complexes are basally targeted remain unknown. Previous studies in the embryonic CNS implied a role of actin-myosin based transport in basal targeting. To investigate whether this is true for post-embryonic NBs, I conducted pharmacological interference experiments. Application of 2, 3-Butanedione monoximine (BDM), a non-muscle myosin inhibitor, or Latrunculin B, an actin polymerisation inhibitor to larval CNS demonstrated a failure in asymmetric segregation of Mira, indicating that both actin and myosin are required for basal targeting of cell fate determinants during NB division. To identify which Drosophila myosin motor(s) are involved, I studied the function of non-muscle myosin II, myosin V and myosin VI, that were previously implicated in basal targeting of the cell fate determinants by RNAi targeted knockdown. Mitotic spindle defects were observed in myosin V and myosin VI knockdown, suggesting a common functional pathway for the two myosin motors. Double knockdown of both myosin V and VI appeared to exacerbate the mitotic spindle defect and affected neural stem cell self-renewal, causing a mild over-proliferation phenotype in the larval central brain, but did not result in tumourigenesis. My data suggest that synergistic activity of myosin V and myosin VI regulate neural stem cell self-renewal and differentiation decision in the post-embryonic central nervous system of Drosophila by regulating mitotic spindle orientation.
Supervisor: Hirth, Frank Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available