Dietary nutrition is required for growth in all animals. When nutrients are abundant, animals increase metabolism to drive growth and proliferation. When nutrients are limited, animals must decrease metabolic processes to conserve energy and promote survival. The evolutionarily conserved Insulin/PI3K and TOR pathways are two important signaling pathways involved in coordinating nutrient availability with the physiological processes that mediate growth and survival. However, the effectors that act downstream of the pathways to control these processes, particularly in vivo, are only beginning to be understood. The fruit fly, Drosophila melanogaster, is one key model system that is used to identify conserved regulatory mechanisms. In this study I explored novel roles for two transcription factors in mediating growth and survival in response to variations in nutrient levels in Drosophila.
In the first part of my study, I explored the role of the transcription factor DREF in mediating response to high nutrient levels. I found that in conditions of high amino acid availability DREF is required for cell autonomous growth downstream of the TOR pathway. I identified the transcriptional regulation of protein synthesis and ribosome biogenesis genes as one mechanism by which DREF mediates growth. I also found that DREF expression in one larval tissue, the nutrient sensing fat-body, is required for non-autonomous growth, through a mechanism that influences systemic insulin signaling.
In the second part of my study, I used an RNAi screen in Drosophila larvae to identify genes that are required to maintain organismal survival in conditions of nutrient deprivation. I found that loss of the transcription factor Hairy led to starvation sensitivity. I further found that hairy mRNA levels are increased upon starvation, and that this is dependent on inhibition of Insulin/PI3K pathway activity. In addition, I explored potential transcriptional targets of Hairy that may be important in mediating starvation survival.
The results contained in this thesis further our understanding of the mechanisms used to couple nutrition availability to metabolic processes in animals. Both DREF and Hairy are conserved in humans and further studies will explore whether these proteins act similarly in higher eukaryotes.