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Published: 2015

Total Pages: 218

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Drosophila has been used for decades to identify and analyze molecular pathways underlying processes such as neurodevelopment and the innate immune response and for modeling complex diseases. In this thesis, I describe the use of Drosophila in two different projects. The first is characterization of a novel signaling pathway regulating growth of the larval neuromuscular junction. The second is the development of an experimental model to investigate neurotoxic effects of radiation exposure during development. Using the larval neuromuscular junction as a model synapse we have identified the lipocalin GLaz, the ortholog of human Apolipoprotein D (hApoD) as a novel regulator of synaptic growth. We have shown that postsynaptic insulin signaling promotes growth of the presynaptic terminal and that insulin signaling is increased in GLaz mutants. Overexpression of GLaz or hApoD in glia results in NMJ undergrowth, which is suppressed by simultaneously increasing insulin signaling in muscle. These studies uncover a novel role for lipocalins in regulation of synaptic growth and support a model in which GLaz is secreted from glia and antagonizes postsynaptic insulin signaling to restrict NMJ growth. We have also used Drosophila to model the neurotoxic side effects of radiation exposure during development as in the treatment for pediatric central nervous system malignancies. We have shown that many of the side effects observed in human patients treated with radiation during development can be modeled in Drosophila. Adult flies exposed to radiation during larval development display reduced survival to adulthood, early death, impaired locomotor behavior, and neurodegeneration. These phenotypes are consistent with premature aging. One hallmark of premature aging is chronic inflammation. Similarly, we find persistent activation of the innate immune system in adult flies that were exposed to radiation during larval development. We further demonstrate that the innate immune response is protective acutely following radiation exposure. Together these data demonstrate that the innate immune pathway is a potential therapeutic target for reducing the side-effects of CRT. The use of this experimental model in genetic screens should facilitate identification of additional radioprotective or radiosensitizing pathways, which may be of further therapeutic value.