title: DREF is required for cell and organismal growth in Drosophila and functions downstream of the nutrition/TOR pathway.
abstract: Nutrient availability is a key determinant of animal growth. The conserved insulin/PI3 kinase and TOR kinase signaling pathways are two of the best characterized regulators of cell and tissue growth in response to nutritional conditions. Studies in Drosophila larvae show that one mechanism by which these pathways drive growth is by regulating the expression of metabolic genes, especially those genes required for protein synthesis. Here we examine a role for the transcription factor DREF in mediating some of these transcriptional and growth responses. We find that loss of DREF leads to a decrease in organismal growth. These effects are in part due to a requirement for DREF function in cell-autonomous growth. We also uncover a non-autonomous role for DREF activity in the larval fat body. Previous studies show that activation of TOR in the fat body couples nutrition to insulin release from the brain; we find that inhibition of DREF in the fat body can phenocopy effects of nutrient deprivation and fat-specific TOR inhibition, leading to a reduction in systemic insulin signaling, delayed larval growth and smaller final size. Using genetic epistasis, we find that DREF is required for growth downstream of TOR, but not insulin/PI3K signaling. Moreover, we show that TOR can control DREF mRNA levels, in part via the transcription factor dMyc. Finally we show that DREF is required for normal expression of many ribosome biogenesis genes, suggesting that one mechanism by which DREF is required for growth is through the control of protein synthetic capacity. Together these findings suggest DREF is an essential transcription factor in the nutritional control of cell and tissue growth during Drosophila development. Given that DREF is conserved, this role may also be important in the control of growth in other animals.
authors.affiliation: Department of Biochemistry and Molecular Biology, and Clark H. Smith Brain Tumour Centre, Southern Alberta Cancer Research Institute, University of Calgary, HRIC, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1.
authors.forename: L E
authors.initials: LE
authors.lastname: Killip
authors.forename: S S
authors.initials: SS
authors.lastname: Grewal
mesh_terms: D000818:Animals; D004330:Drosophila / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007814:Larva / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C099494:Dref protein, Drosophila; C416303:target of rapamycin protein, Drosophila