Drosophila archipelago regulates oxygenhomeostasis via novel roles in tracheogenesis and the hypoxicresponse Open Access

Mortimer, Nathan T (2009)

Permanent URL: https://etd.library.emory.edu/concern/etds/pz50gw351?locale=en
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Abstract

Drosophila archipelago regulates oxygen homeostasis via novel roles in tracheogenesis and the hypoxic response By Nathan T. Mortimer The viability of complex organisms is dependent upon the maintenance of oxygen homeostasis. In Drosophila this is accomplished by the development of the tracheal system, a branched oxygen-conducting network, and by the ability of cells to sense and respond to conditions of lowered oxygen availability, or hypoxia. This hypoxic response is based on the transcriptional activity of the Hypoxia induced factor (HIF) which is conserved from Drosophila to humans. Here we describe novel functions of the Drosophila tumor suppressor homolog archipelago ( ago) in regulating oxygen homeostasis via roles in tracheogenesis and in restricting the hypoxic response. ago mutant embryos display defects in tracheal development due to deregulated activity of the Trachealess transcription factor, illustrating a key regulatory role for ago in the development of the oxygen delivery system. In addition to this developmental role, ago also controls the response to hypoxia in larval and adult Drosophila by regulating the activity of Drosophila HIF. Deregulation of dHIF in ago mutants uncouples activation of the hypoxic response from oxygen deprivation, leading to its ectopic induction in normoxia and altering the organismal response to oxygen deprivation. These findings identify ago as a member of a novel HIF regulatory pathway.

Table of Contents

Table of Contents Chapter 1. Oxygen homeostasis

Page 1 1.A. Introduction Page 2 1.B. The Drosophila tracheal system: a conserved oxygen- conducting organ Page 5 1.C. A conserved mechanism for sensing and responding to hypoxia Page 23 1.D. Hypoxia and HIF signaling in oxygen homeostasis, development and disease Page 29 1.E. Non-canonical regulation of HIF signaling by tumor suppressor proteins Page 40 1.F. Purpose Page 44 Chapter 2. The Drosophila F-box protein Archipelago controls levels of the Trachealess transcription factor in the embryonic tracheal system Page 46 2.A. Introduction Page 47 2.B. ago has a role in embryonic tracheal development Page 51 2.C. ago acts upstream of trachealess and breathless Page 64 2.D. Ago binds Trh and restricts Trh levels in cells Page 73 2.E. Discussion of results Page 78 Chapter 3. Regulation of Drosophila embryonic tracheogenesis by dVHL and hypoxia Page 84 3.A. Introduction Page 85

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