Developmental timing, growth and homeostasis form the cornerstones that shape the genesis and subsequent maintenance of a healthy adult for all multicellular organisms. Understanding the mechanisms that regulate these processes has important implications both from the perspective of our understanding of basic biology and also for our understanding of complex biological disorders involving these processes. My work explores the mechanisms regulating developmental timing, homeostasis and growth using the model organism Drosophila melanogaster. In this thesis I report involvement of three novel players in the regulation of timing, homeostasis and growth in the Drosophila larvae.Firstly, my work unearths the mechanism by which the developmental gap gene, giant, regulates developmental timing in Drosophila larvae. While the effect of Giant (Gt) on larval developmental timing was long known, the mechanism by which Gt exerted this effect was not known. I find that Gt affects developmental timing by influencing the developmental fate of the prothoracicotropic hormone producing PG neurons that are essential for determining the timing of larval developmental transitions. Additionally, I show that Gt is required for PG neuron axon targeting. Secondly, I show that TGF-beta/Activin signaling mediated by the Activin-like ligand Dawdle (Daw) regulates sugar homeostasis, pH balance and mitochondrial metabolism in Drosophila larvae. Canonical signaling by Daw regulates sugar homeostasis primarily by affecting release of insulin in the larvae. The effect of Daw on pH is mediated independently by Daw's action on mitochondrial metabolism and production of metabolic acids. Interestingly, Daw affects both phenotypes in a dose-dependent manner, as demonstrated by both loss-of-function and over-expression/gain-of-function experiments, thereby providing evidence for a hormonal role of Daw in regulating systemic homeostasis. Lastly, I show that eukaryotic uracil salvaging enzyme uracil phospho-ribosyltransferase (UPRT), that was considered inactive in higher eukaryotes including Drosophila, is active in the Drosophila larvae. The Drosophila UPRT homologue, Krishah, can actively incorporate a uracil derivative (4TU) into RNA indicating that the enzyme is active in vivo. Interestingly, I find that Krishah is also essential for larval growth as knocking out the gene leads to impaired larval growth and increased larval and pupal lethality.
University of Minnesota Ph.D. dissertation. August 2013. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisor: Michael B. O'Connor. 1 computer file (PDF); vii, 178 pages, appendices I-IV.
Timing, growth and homeostasis: an anthology of three novel players in Drosophila melanogaster.
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