During the formation of the female gamete the cell cycle events of meiosis must be precisely coordinated with the ongoing differentiation of the oocyte. We use Drosophila melanogaster as a model system to define the pathways that regulate early meiotic progression and oocyte development. To achieve this goal we use forward genetic, biochemical and cell biological approaches. In single celled eukaryotes, the pathways that monitor nutrient availability are central to regulating the meiotic program and spore development. However, how metabolic inputs influence meiotic progression and gametogenesis remains poorly understood in metazoans. Our current studies focus on gaining a mechanistic understanding of how components the SEA/GATOR complex, a newly defined upstream regulator of TORC1, control meiotic progression and growth during oogenesis. TORC1 is a serine/threonine protein kinase that functions as a master regulator of growth and metabolism. Over the last year we defined opposing functions for the SEA complex members Npr2/Npr3 and Mio/Seh1 in the regulation of TORC1 during Drosophila oogenesis. We found that Npr2/Npr3 inhibit TORC1 activity in response to amino acid starvation and are critical to oocyte survival during times of protein scarcity. In the absence of Npr2/Npr3 a brief period of nutritional limitation results in a permanent reduction in female fertility. In contrast, Mio/Seh1 positively regulate TORC1 and are required to oppose the activity of Npr2/Npr3. In mio and seh1 mutants, low TORC1 activity results in a permanent block to oocyte growth and meiotic progression. Epistasis analysis indicates that Mio/Seh1 are upstream of Npr2/Npr3. Our data strongly suggest that a primary function of Mio/Seh1 is to oppose the TORC1 inhibitory activity of Npr2/Npr3. The small GTPase Rheb activates TORC1 on the surface of lysosome. Using live cell imagining of fluorescently tagged proteins, we determined Npr2, Npr3, Mio and Seh1 target to lysosomes and autolysosomes during times of protein scarcity. Thus, Npr2/Npr3 and Mio/Seh1 are well positioned within the cell to regulate TORC1 activity. In summary over the last year our studies have revealed that the tight regulation of TORC1 activity by components of the SEA complex is critical to oocyte development and physiology. This work represents one of the first explorations of the role of SEA complex components within the context of a multi-cellular animal.

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Wei, Youheng; Reveal, Brad; Cai, Weili et al. (2016) The GATOR1 Complex Regulates Metabolic Homeostasis and the Response to Nutrient Stress in Drosophila melanogaster. G3 (Bethesda) 6:3859-3867
Cai, Weili; Wei, Youheng; Jarnik, Michal et al. (2016) The GATOR2 Component Wdr24 Regulates TORC1 Activity and Lysosome Function. PLoS Genet 12:e1006036
Wei, Youheng; Reveal, Brad; Reich, John et al. (2014) TORC1 regulators Iml1/GATOR1 and GATOR2 control meiotic entry and oocyte development in Drosophila. Proc Natl Acad Sci U S A 111:E5670-7
Wei, Y; Lilly, M A (2014) The TORC1 inhibitors Nprl2 and Nprl3 mediate an adaptive response to amino-acid starvation in Drosophila. Cell Death Differ 21:1460-8
Kassis, Judith A; Lilly, Mary A (2013) PRC2 goes solo in the Drosophila female germline. Dev Cell 26:329-30
Mitra, Kasturi; Rikhy, Richa; Lilly, Mary et al. (2012) DRP1-dependent mitochondrial fission initiates follicle cell differentiation during Drosophila oogenesis. J Cell Biol 197:487-97
Senger, Stefania; Csokmay, John; Akbar, Tanveer et al. (2011) The nucleoporin Seh1 forms a complex with Mio and serves an essential tissue-specific function in Drosophila oogenesis. Development 138:2133-42
Ullah, Zakir; Lee, Chrissie Y; Lilly, Mary A et al. (2009) Developmentally programmed endoreduplication in animals. Cell Cycle 8:1501-9
Narbonne-Reveau, Karine; Lilly, Mary (2009) The Cyclin-dependent kinase inhibitor Dacapo promotes genomic stability during premeiotic S phase. Mol Biol Cell 20:1960-9
Mavrakis, Manos; Rikhy, Richa; Lilly, Mary et al. (2008) Fluorescence imaging techniques for studying Drosophila embryo development. Curr Protoc Cell Biol Chapter 4:Unit 4.18

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