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A Drosophila screen for neural proliferation mutants identifies qless, a gene required for CoQ synthesis.

Grant, J.; (2008) A Drosophila screen for neural proliferation mutants identifies qless, a gene required for CoQ synthesis. Doctoral thesis , University of London. Green open access

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Abstract

The final size and shape of the brain is specified during neurogenesis by complex spatiotemporal patterns of cell proliferation and cell death. Many of the developmental genes regulating these two cellular processes remain to be identified. In the holometabolous insect Drosophila, neurogenesis involves distinct embryonic and postembryonic phases. To identify new regulators of Drosophila postembryonic neurogenesis, I conducted two genetic screens. First, a screen of 350 mutagenised chromosomes was used to isolate 22 pupal-lethal mutations associated with an undersized and/or mis-shapened central nervous system. And second, a larger mosaic screen of 1,250 mutagenised chromosomes identified 68 embryonic-lethal mutations altering the number of neurons generated per neural progenitor (neuroblast). Two of the mutations associated with neuroblast clones containing greatly reduced numbers of neurons were mapped to an uncharacterised gene, CG31005 that I have named qless. Sequence analysis indicates that qless encodes a fly orthologue of human prenyl diphosphate synthase subunit 1 (PDSS1), the mitochondrial enzyme that synthesises the isoprenyl side-chains of Coenzyme-Q (CoQ). CoQ is a potent antioxidant and plays a key role in generating cellular ATP via oxidative phosphorylation. Patients with mutations in PDSS1, present a range of pathologies including neural degeneration and mental retardation. In Drosophila, oxidative phosphorylation appears capable of utilising CoQ with anywhere between 4-10 isoprenyl groups as the qless phenotype can be rescued by dietary supplementation with CoQ4, CoQ9 or CoQ 10. Neurons lacking qless activity express activated caspase and their mitochondria display elevated levels of a Cytochrome c epitope associated with apoptosis. Together, these studies of qless shed light on the poorly understood contribution of mitochondria to apoptosis in Drosophila and also provide a genetically tractable model for studying human CoQ deficiencies.

Type: Thesis (Doctoral)
Title: A Drosophila screen for neural proliferation mutants identifies qless, a gene required for CoQ synthesis.
Identifier: PQ ETD:591531
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest. Third party copyright material has been removed from the ethesis
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/1444229
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