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. From our studies we have identified several genes, including missing oocyte (mio) and seh1, which define a new pathway that influences both the maintenance of the meiotic cycle and the oocyte fate. The mio gene was identified in a forward genetic screen for mutants effecting cell cycle regulation and oocyte differentiation in early ovarian cysts. In mio mutants, the oocyte enters the meiotic cycle and accumulates oocyte specific markers. Ultimately, however, mio oocytes exit the meiotic cycle and adopt an alternative nurse cell fate. The mio gene encodes a 975 AA protein that is highly conserved from yeast to humans. Over the last year we have demonstrated that the MIO protein physically associates with the Nucleoporin SEH1. SEH1 is a component of the Nup107-160 complex, the major structural subcomplex of the NPC. The nuclear pore complex (NPC) mediates transport of macromolecules between the nucleus and the cytoplasm. Recent evidence indicates that structural nucleoporins, the building blocks of the NPC, have a variety unanticipated cellular functions. Consistent with these reports we find that the structural nucleoporin SEH1 has an unexpected role during Drosophila oogenesis. As is observed in mio mutants, in seh1mutants a fraction of oocytes fail to maintain the meiotic cycle and develop as pseudo-nurse cells. Moreover, we find that the stability of the MIO protein is greatly diminished in the seh1 mutant background supporting the model that MIO and SEH1 are present in a multi-protein complex. Surprisingly, our characterization of a seh1 null allele indicates that while required in the female germline, seh1 is dispensable for the development of somatic tissues. Our studies support the model that MIO is a novel interacting partner of the conserved nucleoporin SEH1 and add to the growing body of evidence that structural nucleoporins can have novel functions that are independent of their residence at the NPC. Consistent with MIO and SEH1 functioning outside of the context of the NPC, recent reports indicate that MIO and SEH1 homologs from yeast are components of a multi-protein complex called the SEA-complex. The SEA-complex associates with the vacuole, the functional equivalent of lysosomes in metazoans. In yeast several components of the SEA-complex influence mTor activity upon nutrient limitation. At least one member of the SEA-complex, NPR2, functions as a tumor suppressor gene in humans. We have determined that as is observed in yeast, in Drosophila the NPR2 protein associates with both MIO and SEH1. Currently, we are working to define the role of NPR2, MIO, SEH1 and other SEA-complex members, in meiotic progression and growth control in Drosophila.

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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; 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
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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