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Drosophila tor

Adrienne Wang, Jacob Mouser, Jason Pitt, Daniel Promislow, Matt Kaeberlein
Pediatric mitochondrial disorders are a devastating category of diseases caused by deficiencies in mitochondrial function. Leigh Syndrome (LS) is the most common of these diseases with symptoms typically appearing within the first year of birth and progressing rapidly until death, usually by 6-7 years of age. Our lab has recently shown that genetic inhibition of the mechanistic target of rapamycin (TOR) rescues the short lifespan of yeast mutants with defective mitochondrial function, and that pharmacological inhibition of TOR by administration of rapamycin significantly rescues the shortened lifespan, neurological symptoms, and neurodegeneration in a mouse model of LS...
October 11, 2016: Oncotarget
Parisa Kakanj, Bernard Moussian, Sebastian Grönke, Victor Bustos, Sabine A Eming, Linda Partridge, Maria Leptin
The TOR and Insulin/IGF signalling (IIS) network controls growth, metabolism and ageing. Although reducing TOR or insulin signalling can be beneficial for ageing, it can be detrimental for wound healing, but the reasons for this difference are unknown. Here we show that IIS is activated in the cells surrounding an epidermal wound in Drosophila melanogaster larvae, resulting in PI3K activation and redistribution of the transcription factor FOXO. Insulin and TOR signalling are independently necessary for normal wound healing, with FOXO and S6K as their respective effectors...
October 7, 2016: Nature Communications
Olha M Strilbytska, Uliana V Semaniuk, Kenneth B Storey, Bruce A Edgar, Oleh V Lushchak
The TOR (target of rapamycin) signaling pathway and the transcriptional factor Myc play important roles in growth control. Myc acts, in part, as a downstream target of TOR to regulate the activity and functioning of stem cells. Here we explore the role of TOR-Myc axis in stem and progenitor cells in the regulation of lifespan, stress resistance and metabolism in Drosophila. We found that both overexpression of rheb and myc-rheb in midgut stem and progenitor cells decreased the lifespan and starvation resistance of flies...
September 29, 2016: Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology
Marc Amoyel, Kenzo-Hugo Hillion, Shally R Margolis, Erika A Bach
Stem cells reside in niches that provide signals to maintain self-renewal, and differentiation is viewed as a passive process that depends on losing access to these signals. Here we demonstrate that differentiation of somatic cyst stem cells (CySCs) in the Drosophila testis is actively promoted by PI3K/Tor signaling, as CySCs lacking PI3K/Tor activity cannot properly differentiate. We find that an insulin peptide produced by somatic cells immediately outside of the stem cell niche acts locally to promote somatic differentiation through Insulin receptor (InR) activation...
September 15, 2016: Development
Dawei Liu, Zeeshan Shaukat, Tianqi Xu, Donna Denton, Robert Saint, Stephen Gregory
Chromosomal instability (CIN) refers to genomic instability in which cells have gained or lost chromosomes or chromosomal fragments. A high level of CIN is common in solid tumours and is associated with cancer drug resistance and poor prognosis. The impact of CIN-induced stress and the resulting cellular responses are only just beginning to emerge. Using proliferating tissue in Drosophila as a model, we found that autophagy is activated in CIN cells and is necessary for their survival. Specifically, increasing the removal of defective mitochondria by mitophagy is able to lower levels of reactive oxygen species and the resultant cellular damage that is normally seen in CIN cells...
August 31, 2016: Oncotarget
Christie A Bader, Tetyana Shandala, Elizabeth A Carter, Angela Ivask, Taryn Guinan, Shane M Hickey, Melissa V Werrett, Phillip J Wright, Peter V Simpson, Stefano Stagni, Nicolas H Voelcker, Peter A Lay, Massimiliano Massi, Sally E Plush, Douglas A Brooks
Lipids have an important role in many aspects of cell biology, including membrane architecture/compartment formation, intracellular traffic, signalling, hormone regulation, inflammation, energy storage and metabolism. Lipid biology is therefore integrally involved in major human diseases, including metabolic disorders, neurodegenerative diseases, obesity, heart disease, immune disorders and cancers, which commonly display altered lipid transport and metabolism. However, the investigation of these important cellular processes has been limited by the availability of specific tools to visualise lipids in live cells...
2016: PloS One
Anindita Mukherjee, Bindi Patel, Hiroshi Koga, Ana Maria Cuervo, Andreas Jenny
Autophagy delivers cytosolic components to lysosomes for degradation and is thus essential for cellular homeostasis and to cope with different stressors. As such, autophagy counteracts various human diseases and its reduction leads to aging-like phenotypes. Macroautophagy (MA) can selectively degrade organelles or aggregated proteins, whereas selective degradation of single proteins has only been described for chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI). These 2 autophagic pathways, are specific for proteins containing KFERQ-related targeting motifs...
August 3, 2016: Autophagy
Martin R Schmid, Ines Anderl, Hoa T M Vo, Susanna Valanne, Hairu Yang, Jesper Kronhamn, Mika Rämet, Tor Erik Rusten, Dan Hultmark
To understand how Toll signaling controls the activation of a cellular immune response in Drosophila blood cells (hemocytes), we carried out a genetic modifier screen, looking for deletions that suppress or enhance the mobilization of sessile hemocytes by the gain-of-function mutation Toll10b (Tl10b). Here we describe the results from chromosome arm 3R, where five regions strongly suppressed this phenotype. We identified the specific genes immune response deficient 1 (ird1), headcase (hdc) and possibly Rab23 as suppressors, and we studied the role of ird1 in more detail...
2016: PloS One
Murni Tio, Rujing Wen, Yih Lin Lim, Huashan Wang, Shuo-Chien Ling, Yi Zhao, Eng-King Tan
Essential tremor (ET) is one of the most common adult-onset neurological disorders which produce motor and non-motor symptoms. To date, there are no gold standard pathological hallmarks of ET, and despite a strong genetic contribution toward ET development, only a few pathogenic mutations have been identified. Recently, a pathogenic FUS-Q290X mutation has been reported in a large ET-affected family; however, the pathophysiologic mechanism underlying FUS-linked ET is unknown. Here, we generated transgenic Drosophila expressing hFUS-WT and hFUS-Q290X and targeted their expression in different tissues...
July 9, 2016: Human Genetics
E Thomas Danielsen, Morten E Moeller, Naoki Yamanaka, Qiuxiang Ou, Janne M Laursen, Caecilie Soenderholm, Ran Zhuo, Brian Phelps, Kevin Tang, Jie Zeng, Shu Kondo, Christian H Nielsen, Eva B Harvald, Nils J Faergeman, Macy J Haley, Kyle A O'Connor, Kirst King-Jones, Michael B O'Connor, Kim F Rewitz
Steroid hormones control important developmental processes and are linked to many diseases. To systematically identify genes and pathways required for steroid production, we performed a Drosophila genome-wide in vivo RNAi screen and identified 1,906 genes with potential roles in steroidogenesis and developmental timing. Here, we use our screen as a resource to identify mechanisms regulating intracellular levels of cholesterol, a substrate for steroidogenesis. We identify a conserved fatty acid elongase that underlies a mechanism that adjusts cholesterol trafficking and steroidogenesis with nutrition and developmental programs...
June 20, 2016: Developmental Cell
Nizar A Hussein, Taylor L Delaney, Brittany L Tounsel, Faith L W Liebl
The proper localization and synthesis of postsynaptic glutamate receptors are essential for synaptic plasticity. Synaptic translation initiation is thought to occur via the target of rapamycin (TOR) and mitogen-activated protein kinase signal-integrating kinase (Mnk) signaling pathways, which is downstream of extracellular-regulated kinase (ERK). We used the model glutamatergic synapse, the Drosophila neuromuscular junction, to better understand the roles of the Mnk and TOR signaling pathways in synapse development...
2016: Journal of Experimental Neuroscience
Thao Phuong Le, Linh Thuong Vuong, Ah-Ram Kim, Ya-Chieh Hsu, Kwang-Wook Choi
14-3-3 family proteins regulate multiple signalling pathways. Understanding biological functions of 14-3-3 proteins has been limited by the functional redundancy of conserved isotypes. Here we provide evidence that 14-3-3 proteins regulate two interacting components of Tor signalling in Drosophila, translationally controlled tumour protein (Tctp) and Rheb GTPase. Single knockdown of 14-3-3ɛ or 14-3-3ζ isoform does not show obvious defects in organ development but causes synergistic genetic interaction with Tctp and Rheb to impair tissue growth...
2016: Nature Communications
Yadav Kuleesha, Wee Choo Puah, Martin Wasser
BACKGROUND: The contribution of programmed cell death (PCD) to muscle wasting disorders remains a matter of debate. Drosophila melanogaster metamorphosis offers the opportunity to study muscle cell death in the context of development. Using live cell imaging of the abdomen, two groups of larval muscles can be observed, doomed muscles that undergo histolysis and persistent muscles that are remodelled and survive into adulthood. METHOD: To identify and characterize genes that control the decision between survival and cell death of muscles, we developed a method comprising in vivo imaging, targeted gene perturbation and time-lapse image analysis...
2016: BMC Developmental Biology
Jong Woo Jun, Gangsik Han, Hyun Myoung Yun, Gang Jun Lee, Seogang Hyun
Torso is a receptor tyrosine kinase whose localized activation at the termini of the Drosophila embryo is mediated by its ligand, Trunk. Recent studies have unveiled a second function of Torso in the larval prothoracic gland (PG) as the receptor for the prothoracicotropic hormone, which triggers pupariation. As such, inhibition of Torso in the PG prolongs the larval growth period, thereby increasing the final pupa size. Here, we report that Torso also acts in the larval fat body, regulating body size in a manner opposite from that of Torso in PG...
August 2016: Journal of Comparative Physiology. B, Biochemical, Systemic, and Environmental Physiology
Yadav Kuleesha, Wee Choo Puah, Martin Wasser
Genes controlling muscle size and survival play important roles in muscle wasting diseases. In Drosophila melanogaster metamorphosis, larval abdominal muscles undergo two developmental fates. While a doomed population is eliminated by cell death, another persistent group is remodelled and survives into adulthood. To identify and characterize genes involved in the development of remodelled muscles, we devised a workflow consisting of in vivo imaging, targeted gene perturbation and quantitative image analysis...
February 2016: Royal Society Open Science
Foivos-Filippos Tsokanos, Marie-Astrid Albert, Constantinos Demetriades, Kerstin Spirohn, Michael Boutros, Aurelio A Teleman
Amino acids regulate TOR complex 1 (TORC1) via two counteracting mechanisms, one activating and one inactivating. The presence of amino acids causes TORC1 recruitment to lysosomes where TORC1 is activated by binding Rheb. How the absence of amino acids inactivates TORC1 is less well understood. Amino acid starvation recruits the TSC1/TSC2 complex to the vicinity of TORC1 to inhibit Rheb; however, the upstream mechanisms regulating TSC2 are not known. We identify here the eIF4A-containing eIF4F translation initiation complex as an upstream regulator of TSC2 in response to amino acid withdrawal in Drosophila We find that TORC1 and translation preinitiation complexes bind each other...
May 17, 2016: EMBO Journal
Patrick Fischer, Anette Preiss, Anja C Nagel
Size and weight control is a tightly regulated process, involving the highly conserved Insulin receptor/target of rapamycin (InR/TOR) signaling cascade. We recently identified Cyclin G (CycG) as an important modulator of InR/TOR signaling activity in Drosophila. cycG mutant flies are underweight and show a disturbed fat metabolism resembling TOR mutants. In fact, InR/TOR signaling activity is disturbed in cycG mutants at the level of Akt1, the central kinase linking InR and TORC1. Akt1 is negatively regulated by protein phosphatase PP2A...
January 2, 2016: Fly
Takashi Koyama, Christen K Mirth
In Drosophila, the fat body, functionally equivalent to the mammalian liver and adipocytes, plays a central role in regulating systemic growth in response to nutrition. The fat body senses intracellular amino acids through Target of Rapamycin (TOR) signaling, and produces an unidentified humoral factor(s) to regulate insulin-like peptide (ILP) synthesis and/or secretion in the insulin-producing cells. Here, we find that two peptides, Growth-Blocking Peptide (GBP1) and CG11395 (GBP2), are produced in the fat body in response to amino acids and TOR signaling...
February 2016: PLoS Biology
Stewart Frankel, Jared Woods, Tahereh Ziafazeli, Blanka Rogina
Single-gene mutations that extend longevity have revealed regulatory pathways related to aging and longevity. RPD3 is a conserved histone deacetylase (Class I HDAC). Previously we showed that Drosophila rpd3 mutations increase longevity. Here we tested the longevity effects of RPD3 on multiple nutrient levels. Dietary restriction (DR) has additive effects on RPD3-mediated longevity extension, but the effect may be modestly attenuated relative to controls. RPD3 and DR therefore appear to operate by distinct but interacting mechanisms...
December 2015: Aging
Sandra Schmitt, Rupali Ugrankar, Stephanie E Greene, Meenakshi Prajapati, Michael Lehmann
Lipin proteins have key functions in lipid metabolism, acting as both phosphatidate phosphatases (PAPs) and nuclear regulators of gene expression. We show that the insulin and TORC1 pathways independently control functions of Drosophila Lipin (dLipin). Reduced signaling through the insulin receptor strongly enhanced defects caused by dLipin deficiency in fat body development, whereas reduced signaling through TORC1 led to translocation of dLipin into the nucleus. Reduced expression of dLipin resulted in decreased signaling through the insulin-receptor-controlled PI3K-Akt pathway and increased hemolymph sugar levels...
December 1, 2015: Journal of Cell Science
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