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Apoptosis in the nematode C. elegans

Applicant Hengartner Michael
Number 143932
Funding scheme Project funding
Research institution Institut für Molekulare Biologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Genetics
Start/End 01.10.2012 - 30.09.2016
Approved amount 930'000.00
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All Disciplines (4)

Discipline
Genetics
Embryology, Developmental Biology
Molecular Biology
Cellular Biology, Cytology

Keywords (10)

vincristine; C. elegans; chemotherapy; germ line; Phagocytosis; apoptosis; programmed cell death; genotoxic stress; model organism; cancer

Lay Summary (German)

Lead
Der menschliche Körper besteht aus etwa 100 Billionen Zellen, die eng miteinander kooperieren. Damit unser Körper optimal funktioniert, müssen unter gewissen Umständen Zellen sich selbst das Leben nehmen. Dieser Selbstmord, auch programmierter Zelltod oder Apoptose genannt, kommt ins Spiel wenn zum Beispiel eine Zelle durch einen Virus infiziert wurde. Fehler im Apoptose-Programm können zu verschiedenen Krankheiten führen, z.B. Krebs oder Autoimmun-Krankheiten.
Lay summary

Apoptose findet man nicht nur beim Menschen, sondern auch bei einfacheren Tierarten.  In unserer Forschungsgruppe fokussieren wir uns auf die Apoptose beim Fadenwurm Caenorhabditis elegans, einen oft-benutzten Modellorganismus.  Frühere Untersuchungen haben gezeigt, dass der Prozess der Apoptose zwischen Mensch und „Wurm“ zum grossen Teil konserviert ist, so dass Erkenntnisse, die mit C. elegans gewonnen werden, sehr oft auch für den Menschen relevant sind.

In diesem Forschungsprojekt untersuchen wir zwei unterschiedliche Aspekte der Apoptose. 

  1. Welche Signalwege führen in C. elegans nach Beschädigung des Erbguts (DNA) zu Apoptose?  Sind diese Signalwege konserviert und auch beim Menschen vorhanden?  Wenn ja, sind sie möglicherweise an der Entwicklung von Krebs beteiligt?
  2. Wie werden sterbende Zellen von ihren Nachbarn erkannt und eliminiert?  Was sind die Signale, die von sterbenden Zellen kommen und wie wirken diese auf die Nachbarn-Zellen? 

Unser Forschungsprogramm soll uns zu einem besseren Verständnis der Apoptose beim Modellorganismus C. elegans verhelfen.  Auf Grund der Konservierung des Prozesses könnten diese Ergebnisse auch für den Menschen relevant sein.

Direct link to Lay Summary Last update: 17.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Loss of Acetylcholine Signaling Reduces Cell Clearance Deficiencies in Caenorhabditis elegans
Pinto Sérgio M., Almendinger Johann, Cabello Juan, Hengartner Michael O. (2016), Loss of Acetylcholine Signaling Reduces Cell Clearance Deficiencies in Caenorhabditis elegans, in PLOS ONE, 11(2), e0149274-e0149274.
Loss of Acetylcholine Signaling Reduces Cell Clearance Deficiencies in Caenorhabditis elegans.
Pinto Sérgio M, Almendinger Johann, Cabello Juan, Hengartner Michael O (2016), Loss of Acetylcholine Signaling Reduces Cell Clearance Deficiencies in Caenorhabditis elegans., in PloS one, 11(2), 0149274-0149274.
Natural Genetic Variation Differentially Affects the Proteome and Transcriptome in Caenorhabditis elegans
Kamkina Polina, Snoek L. Basten, Grossmann Jonas, Volkers Rita J. M., Sterken Mark G., Daube Michael, Roschitzki Bernd, Fortes Claudia, Schlapbach Ralph, Roth Alexander, von Mering Christian, Hengartner Michael O., Schrimpf Sabine P., Kammenga Jan E. (2016), Natural Genetic Variation Differentially Affects the Proteome and Transcriptome in Caenorhabditis elegans, in Molecular & Cellular Proteomics, 15(5), 1670-1680.
Natural Genetic Variation Influences Protein Abundances in C. elegans Developmental Signalling Pathways
Singh Kapil Dev, Roschitzki Bernd, Snoek L. Basten, Grossmann Jonas, Zheng Xue, Elvin Mark, Kamkina Polina, Schrimpf Sabine P., Poulin Gino B., Kammenga Jan E., Hengartner Michael O. (2016), Natural Genetic Variation Influences Protein Abundances in C. elegans Developmental Signalling Pathways, in PLOS ONE, 11(3), e0149418-e0149418.
Post-transcriptional control of executioner caspases by RNA-binding proteins.
Subasic Deni, Stoeger Thomas, Eisenring Seline, Matia-González Ana M, Imig Jochen, Zheng Xue, Xiong Lei, Gisler Pascal, Eberhard Ralf, Holtackers René, Gerber André P, Pelkmans Lucas, Hengartner Michael O (2016), Post-transcriptional control of executioner caspases by RNA-binding proteins., in Genes & development, 30(19), 2213-2225.
Essential versus accessory aspects of cell death: recommendations of the NCCD 2015.
Galluzzi L, Bravo-San Pedro J M, Vitale I, Aaronson S A, Abrams J M, Adam D, Alnemri E S, Altucci L, Andrews D, Annicchiarico-Petruzzelli M, Baehrecke E H, Bazan N G, Bertrand M J, Bianchi K, Blagosklonny M V, Blomgren K, Borner C, Bredesen D E, Brenner C, Campanella M, Candi E, Cecconi F, Chan F K, Chandel N S, Cheng E H (2015), Essential versus accessory aspects of cell death: recommendations of the NCCD 2015., in Cell death and differentiation, 22(1), 58-73.
A novel mouse model for inhibition of DOHH-mediated hypusine modification reveals a crucial function in embryonic development, proliferation and oncogenic transformation.
Sievert Henning, Pällmann Nora, Miller Katharine K, Hermans-Borgmeyer Irm, Venz Simone, Sendoel Ataman, Preukschas Michael, Schweizer Michaela, Boettcher Steffen, Janiesch P Christoph, Streichert Thomas, Walther Reinhard, Hengartner Michael O, Manz Markus G, Brümmendorf Tim H, Bokemeyer Carsten, Braig Melanie, Hauber Joachim, Duncan Kent E, Balabanov Stefan (2014), A novel mouse model for inhibition of DOHH-mediated hypusine modification reveals a crucial function in embryonic development, proliferation and oncogenic transformation., in Disease models & mechanisms, 7(8), 963-76.
Apoptotic cell death under hypoxia.
Sendoel Ataman, Hengartner Michael O (2014), Apoptotic cell death under hypoxia., in Physiology (Bethesda, Md.), 29(3), 168-76.
DEPDC1/LET-99 participates in an evolutionarily conserved pathway for anti-tubulin drug-induced apoptosis.
Sendoel Ataman, Maida Simona, Zheng Xue, Teo Youjin, Stergiou Lilli, Rossi Carlo-Alberto, Subasic Deni, Pinto Sergio M, Kinchen Jason M, Shi Moyin, Boettcher Steffen, Meyer Joel N, Manz Markus G, Bano Daniele, Hengartner Michael O (2014), DEPDC1/LET-99 participates in an evolutionarily conserved pathway for anti-tubulin drug-induced apoptosis., in Nature cell biology, 16(8), 812-20.
Small GTPase CDC-42 promotes apoptotic cell corpse clearance in response to PAT-2 and CED-1 in C. elegans
Neukomm L J, Zeng S, Frei A P, Huegli P A, Hengartner M O (2014), Small GTPase CDC-42 promotes apoptotic cell corpse clearance in response to PAT-2 and CED-1 in C. elegans, in Cell Death and Differentiation, 21(6), 845-853.
Mitochondria as a target of environmental toxicants.
Meyer Joel N, Leung Maxwell C K, Rooney John P, Sendoel Ataman, Hengartner Michael O, Kisby Glen E, Bess Amanda S (2013), Mitochondria as a target of environmental toxicants., in Toxicological sciences : an official journal of the Society of Toxicology, 134(1), 1-17.
Model organisms proteomics--from holobionts to human nutrition.
Tholey Andreas, Treitz Christian, Kussmann Martin, Bendixen Emöke, Schrimpf Sabine P, Hengartner Michael O (2013), Model organisms proteomics--from holobionts to human nutrition., in Proteomics, 13(17), 2537-41.
Ribosome synthesis and MAPK activity modulate ionizing radiation-induced germ cell apoptosis in Caenorhabditis elegans.
Eberhard Ralf, Stergiou Lilli, Hofmann E Randal, Hofmann Jen, Haenni Simon, Teo Youjin, Furger André, Hengartner Michael O (2013), Ribosome synthesis and MAPK activity modulate ionizing radiation-induced germ cell apoptosis in Caenorhabditis elegans., in PLoS genetics, 9(11), 1003943-1003943.
WormQTL--public archive and analysis web portal for natural variation data in Caenorhabditis spp.
Snoek L Basten, Van der Velde K Joeri, Arends Danny, Li Yang, Beyer Antje, Elvin Mark, Fisher Jasmin, Hajnal Alex, Hengartner Michael O, Poulin Gino B, Rodriguez Miriam, Schmid Tobias, Schrimpf Sabine, Xue Feng, Jansen Ritsert C, Kammenga Jan E, Swertz Morris A (2013), WormQTL--public archive and analysis web portal for natural variation data in Caenorhabditis spp., in Nucleic acids research, 41(Database i), 738-43.
Cleaning up the mess: cell corpse clearance in Caenorhabditis elegans.
Pinto Sérgio Morgado, Hengartner Michael Otmar (2012), Cleaning up the mess: cell corpse clearance in Caenorhabditis elegans., in Current opinion in cell biology, 24(6), 881-8.
Differential regulation of DNA damage response activation between somatic and germline cells in Caenorhabditis elegans.
Vermezovic J, Stergiou L, Hengartner M O, d'Adda di Fagagna F (2012), Differential regulation of DNA damage response activation between somatic and germline cells in Caenorhabditis elegans., in Cell death and differentiation, 19(11), 1847-55.

Collaboration

Group / person Country
Types of collaboration
Kodi Ravichandran United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Daniele Bano Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Lucas Pelkmans Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Ruedi Aebersold, ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Associated projects

Number Title Start Funding scheme
146328 Large-Scale Single Organism Studies in Caenorhabditis Elegans 01.06.2013 Interdisciplinary projects
141942 Post-transcriptional regulation of germ cell apoptosis in C. elegans 01.11.2012 Sinergia
128675 Apoptosis in the nematode C. elegans 01.10.2009 Project funding

Abstract

Apoptosis is an important component of animal development and homeostasis. Defects in the regulation of the apoptotic program have been implicated in the aetiology of cancer, autoimmune diseases, myocardial heart infarct, stroke, and neurodegenerative diseases. The small nematode Caenorhabditis elegans has been used with great success as a model organism for the genetic analysis of programmed cell death. Extensive studies in this organism have shown that the molecular machinery responsible for apoptotic death is conserved between nematodes and humans. Thus, information gained about nematode cell death is likely to shed light on the regulation of apoptosis in mammals. In this grant application, we propose to use C. elegans as a genetic model system to study two interesting and important questions related to apoptosis. In Project A, we will dissect the signaling pathway that mediates germ cell apoptosis in response to vincristine treatment. Antitubulin chemotherapeutics such as vincristine can suppress microtubule dynamics, resulting in mitotic arrest and apoptosis. How defects in microtubule dynamics induce apoptosis is however still largely unclear. We recently found that the C. elegans gene LET-99 and its human homologue are specifically required for vincristine-induced apoptosis. To better understand this process, we will:• Identify and characterize the kinase signaling pathway that mediates vincristine- and LET-99-dependent apoptosis.• Identify and characterize of LET-99-interacting proteins in the C. elegans germ line.• Identify and characterize additional modulators of vincristine-induced germ cell apoptosis.In Project B, we investigate continue our analysis of how apoptotic cells are recognized and cleared from the body. As is the case for the apoptotic program, the molecular program that mediates clearance of apoptotic cells has been suggested to play important roles in the maintenance of homeostasis. We recently set up a sensitive new GFP-based genetic screen for mutations that modulate either the survival or clearance of six specific neurons (Pn.aap cells) in C. elegans. Using this assay, we isolated over 18 strains with reduced Pn.aap cells and 8 strains with increased Pn.aap cells. In the current funding period, we will: • Determine the biological process affected by mutations that alter Pn.aap cell numbers.• Identify the genes affected by these new “Pn.aap mutations”.• Characterize at the genetic and molecular levels the most interesting new genes isolated in this screen.The work that we propose to do in this grant proposal should significantly improve our understanding of the signaling pathway that mediates apoptosis following vincristine treatment, and might identify new genes that, when altered, can contribute to the development to resistance to antitubulin treatment. We also expect to gain new insights into the signaling pathways that mediate apoptotic cell recognition, uptake, and degradation. Because apoptotic pathways are largely conserved through evolution, we expect that our findings will indirectly also improve our understanding of these processes in humans.
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