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Genetic, genomic and molecular studies of signaling pathways controlling ecdysone biosynthesis in Drosophila melanogaster Open Access


Other title
not applicable
ring gland
steroid hormone
nuclear receptor
Type of item
Degree grantor
University of Alberta
Author or creator
Ou, Qiuxiang
Supervisor and department
King-Jones, Kirst (Biological Sciences)
Examining committee member and department
King-Jones, Kirst (Biological Sciences)
Lipshitz, Howard (Molecular Genetics, University of Toronto)
Waskiewicz, Andrew (Biological Sciences)
Campbell, Shelagh (Biological Sciences)
Nargang, Frank (Biological Sciences)
Department of Biological Sciences
Molecular Biology and Genetics
Date accepted
Graduation date
Doctor of Philosophy
Degree level
In insects, periodic pulses of the molting hormone ecdysone control all major developmental transitions such as the molts and metamorphosis. Ecdysone, a steroid hormone, is produced in the prothoracic gland during larval and pupal development of Drosophila. While we have a relatively good understanding of the enzymatic steps involved in ecdysone synthesis, the signaling pathways controlling this process remain poorly characterized. It has long been known that the synthesis and release of ecdysone is under the control of a brain neuropeptide called PTTH, which stimulates ecdysone synthesis by activating the Ras/Raf/MAPK cascade through its receptor Torso in prothoracic gland cells. However, direct downstream targets of this pathway remained elusive. My work demonstrated that Drosophila Hormone Receptor 4 (DHR4) represents a key target of the PTTH signaling cascade and plays a key role in appropriately timing ecdysone pulses by oscillating between nucleus and cytoplasm of prothoracic gland cells. I also showed that DHR4 negatively regulates the expression of Cyp6t3, a previously uncharacterized enzyme required for ecdysone synthesis. Therefore, I proposed that nuclear DHR4 inhibits ecdysone synthesis through repression of Cyp6t3 and possibly other target genes, and that this repressive function can be overturned by the removal of DHR4 from nuclei of prothoracic gland cells via activating the PTTH pathway. A parallel project was aimed at identifying novel components required for ecdysone production in the prothoracic gland. For this, I performed whole-genome microarray analysis of hand-dissected ring glands (which harbor the prothoracic gland) and compared the signal to microarrays of whole larvae samples, which allowed me to identify genes with specific expression in the ring gland. The function of the highest-scoring genes (~100) were then analyzed via prothoracic gland-specific RNA interference, which yielded 25 genes that have likely novel roles in ecdysone synthesis. Among these, I studied a gene with homology to human neurotrophins in more detail. Vertebrate neurotrophins are signaling molecules that carry out neuroprotective functions during brain development. Here, I describe a novel developmental role for a Drosophila neurotrophin in controlling ecdysone synthesis in the prothoracic gland. This finding represents a new layer of steroid hormone regulation, and broadens our current perspective of the mechanisms by which insect metamorphosis is regulated.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Ou Q, Magico A, King-Jones K (2011) Nuclear Receptor DHR4 Controls the Timing of Steroid Hormone Pulses During Drosophila Development. PLoS Biol 9(9): e1001160. doi:10.1371/journal.pbio.1001160

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