Molecular regulation of Insulin signaling in nutrient stress response in Drosophila.

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Organ growth is one of the most fundamental biological processes during metazoan development and is tightly regulated by multiple mechanisms. A key factor that determines adult size in the fruit fly Drosophila is nutrient availability during the larval growth phase. Reduced nutrition decreases larval growth, and eventually the final size of an adult fly. This research project aims to understand how animals adjust their growth rate in response to nutrient availability. It will provide new insights into the molecular mechanisms underlying nutrient stress response during animal development. In addition, this project will provide a platform for broadening participation of students under-represented in STEM fields at multiple levels. The results of this research will be integrated into workshops, seminars, and courses for undergraduate and graduate students, which will inspire prospective students to pursue education and careers in biological research.The insulin signaling pathway plays critical roles in controlling cell growth, proliferation and metabolism in response to intracellular and extracellular stimuli. In Drosophila, PTEN mutant cells showed a strong growth advantage under nutrient starvation conditions. Strikingly, while the increase of PTEN mutant eye size was mainly caused by enlarged cell size under nutrient rich conditions, the overgrowth of the PTEN mutant eye under nutrient starvation conditions was largely due to massively increased cell number. How reduced nutrition primarily affects the proliferation potential of PTEN mutant cells remains unclear. Drosophila Headcase (Hdc) is a nutrient stress specific growth regulator that regulates cell cycle progression. Hdc genetically interacts with multiple insulin signaling pathway components. In addition, Hdc protein is phosphorylated by Akt, a key protein kinase of the insulin signaling pathway. The central hypothesis of this project is that Hdc functions as a novel downstream regulator of the insulin signaling pathway and mediates PTEN regulated nutrient stress response. This hypothesis will be tested by three specific aims: (1) define the upstream signal that links nutritional status to Hdc growth inhibition function, (2) investigate the molecular regulation of Hdc by Akt induced phosphorylation, and (3) determine the role of Hdc in PTEN mediated nutrient stress response. The proposed research is expected to reveal novel molecular architecture of the insulin signaling pathway in nutrient stress response. This project will provide a platform for broadening participation of students that are under-represented in STEM fields.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.