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19 results on '"MESH: Feedback, Physiological"'

1. STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling

Author

Frédéric Colland, Kei-ichiro Arimoto, Ming Yan, Dong-Er Zhang, Sandra Pellegrini, Stephan Wilmes, Yue Zhang, Jacob Piehler, Samuel A Stoner, Sayuri Miyauchi, Jürgen J. Heinisch, Sara Löchte, Christoph Burkart, Zhi Li, Jun-Bao Fan, University of California [San Diego] (UC San Diego), University of California, Fachhochschule Osnabrück, Signalisation des Cytokines - Cytokine Signaling, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hybrigenics [Paris], Hybrigenics, This study was supported by NIH R01HL091549 and R01CA177305 to D.-E.Z. and SFB 944 from the DFG to J.P. and J.J.H., University of California (UC), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Li, Zhi

Subjects
0301 basic medicine, MESH: Signal Transduction, MESH: Interferon Type I, MESH: Feedback, Physiological, Receptor, Interferon alpha-beta, Medical and Health Sciences, Interferon alpha-beta, MESH: Mutant Proteins, Mice, 0302 clinical medicine, Structural Biology, Interferon, MESH: STAT2 Transcription Factor, MESH: Animals, STAT2, Receptor, MESH: Endopeptidases, Feedback, Physiological, Tumor, biology, MESH: Immunoblotting, Effector, Biological Sciences, 3. Good health, Cell biology, 030220 oncology & carcinogenesis, Interferon Type I, MESH: Protein Domains, Signal transduction, Ubiquitin Thiolesterase, medicine.drug, Protein Binding, Signal Transduction, Cell signaling, MESH: Cell Line, Tumor, Physiological, Immunoblotting, Biophysics, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Two-Hybrid System Techniques, Article, Cell Line, Feedback, 03 medical and health sciences, Immune system, Protein Domains, Cell Line, Tumor, Two-Hybrid System Techniques, Endopeptidases, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, MESH: Protein Binding, MESH: Receptor, Interferon alpha-beta, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, MESH: Mice, MESH: Humans, STAT2 Transcription Factor, 030104 developmental biology, Chemical Sciences, Cancer research, biology.protein, Mutant Proteins, Interferon type I, Developmental Biology
Abstract

International audience; Type I interferons (IFNs) are multifunctional cytokines that regulate immune responses and cellular functions but also can have detrimental effects on human health. A tight regulatory network therefore controls IFN signaling, which in turn may interfere with medical interventions. The JAK-STAT signaling pathway transmits the IFN extracellular signal to the nucleus, thus resulting in alterations in gene expression. STAT2 is a well-known essential and specific positive effector of type I IFN signaling. Here, we report that STAT2 is also a previously unrecognized, crucial component of the USP18-mediated negative-feedback control in both human and mouse cells. We found that STAT2 recruits USP18 to the type I IFN receptor subunit IFNAR2 via its constitutive membrane-distal STAT2-binding site. This mechanistic coupling of effector and negative-feedback functions of STAT2 may provide novel strategies for treatment of IFN-signaling-related human diseases.

Published
2017

2. Increased adaptive immune responses and proper feedback regulation protect against clinical dengue

Author

Anavaj Sakuntabhai, Arnaud Tarantola, Veasna Duong, Philippe Buchy, Noémie Courtejoie, Philippe Dussart, Ahmed Tawfik, Sivlin Ung, Kevin Bleakley, Etienne Simon-Loriere, Sowath Ly, Matthieu Prot, Isabelle Casademont, Tineke Cantaert, Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Unité d'Épidémiologie et de Santé Publique [Phnom Penh], Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Laboratoire de Mathématiques d'Orsay (LM-Orsay), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria), GlaxoSmithKline, Glaxo Smith Kline, Unité de Virologie / Virology Unit [Phnom Penh], This work was supported by the European Union Seventh Framework Programme (FP7/2007-2011) under grant agreement 282378 and the PTR373 funding of Institut Pasteur International Network., European Project: 282378, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Génétique fonctionnelle des Maladies infectieuses, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur du Cambodge-Réseau International des Instituts Pasteur ( RIIP ), Unité d'Épidémiologie et de Santé Publique, Institut National de Recherche en Informatique et en Automatique ( Inria ), Département de Mathématiques [ORSAY], Université Paris-Sud - Paris 11 ( UP11 ), GlaxoSmithKline (GSK) Vaccine, European Project : 282378, and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, MESH: Inflammation, Transcription, Genetic, MESH: Feedback, Physiological, T-Lymphocytes, viruses, Apoptosis, MESH: Dengue, Adaptive Immunity, Dengue virus, Antibodies, Viral, Lymphocyte Activation, medicine.disease_cause, Dengue fever, Dengue, 0302 clinical medicine, [STAT.ML]Statistics [stat]/Machine Learning [stat.ML], MESH: Demography, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Child, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Child, MESH: Treatment Outcome, Feedback, Physiological, Antigen Presentation, education.field_of_study, MESH: Cytokines, MESH: Plasma Cells, Cell Differentiation, General Medicine, Viral Load, MESH: Gene Expression Regulation, 3. Good health, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Treatment Outcome, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Acute Disease, Cytokines, MESH: Acute Disease, MESH: Immunity, Innate, medicine.symptom, MESH: Viral Load, Viral load, MESH: Cell Differentiation, T cell, Plasma Cells, 030231 tropical medicine, Population, Asymptomatic, 03 medical and health sciences, Immune system, medicine, Humans, Viremia, MESH: Viremia, Quantitative Biology - Populations and Evolution, education, MESH: Lymphocyte Activation, Demography, Inflammation, Innate immune system, MESH: Humans, [ SDV ] Life Sciences [q-bio], business.industry, MESH: Transcription, Genetic, MESH: Apoptosis, Populations and Evolution (q-bio.PE), biochemical phenomena, metabolism, and nutrition, medicine.disease, Immunity, Innate, 030104 developmental biology, MESH: T-Lymphocytes, Gene Expression Regulation, FOS: Biological sciences, Immunology, MESH: Antigen Presentation, business, MESH: Adaptive Immunity, MESH: Antibodies, Viral
Abstract

International audience; Clinical symptoms of dengue virus (DENV) infection, the most prevalent arthropod-borne viral disease, range from classical mild dengue fever to severe, life-threatening dengue shock syndrome. However, most DENV infections cause few or no symptoms. Asymptomatic DENV-infected patients provide a unique opportunity to decipher the host immune responses leading to virus elimination without negative impact on an individual's health. We used an integrated approach of transcriptional profiling and immunological analysis to compare a Cambodian population of strictly asymptomatic viremic individuals with clinical dengue patients. Whereas inflammatory pathways and innate immune response pathways were similar between asymptomatic individuals and clinical dengue patients, expression of proteins related to antigen presentation and subsequent T cell and B cell activation pathways was differentially regulated, independent of viral load and previous DENV infection history. Feedback mechanisms controlled the immune response in asymptomatic viremic individuals, as demonstrated by increased activation of T cell apoptosis-related pathways and FcγRIIB (Fcγ receptor IIB) signaling associated with decreased anti-DENV-specific antibody concentrations. Together, our data illustrate that symptom-free DENV infection in children is associated with increased activation of the adaptive immune compartment and proper control mechanisms, leading to elimination of viral infection without excessive immune activation, with implications for novel vaccine development strategies.

Published
2017

3. The Legionella pneumophila genome evolved to accommodate multiple regulatory mechanisms controlled by the CsrA-system

Author

Sahr, Tobias, Rusniok, Christophe, Impens, Francis, Oliva, Giulia, Sismeiro, Odile, Coppée, Jean-Yves, Buchrieser, Carmen, Biologie des Bactéries intracellulaires - Biology of Intracellular Bacteria, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Interactions Bactéries-Cellules (UIBC), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Transcriptome et Epigénome (PF2), Institut Pasteur [Paris] (IP), Work in the CB laboratory is financed by the Institut Pasteur, the Institut Carnot-Pasteur MI, the French Region Ile de France (DIM Malinf), the grant n°ANR-10-LABX-62-IBEID, the Fondation pour la Recherche Médicale (FRM) grant N° DEQ20120323697 and the Pasteur-Weizmann consortium « The roles of non-coding RNAs in regulation of microbial life styles and virulence ». The Transcriptome and EpiGenome Platform is a member of the France Génomique consortium (ANR10-NBS-09-08). FI received financial support from a Pasteur-Roux Fellowship The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], Biologie des Bactéries intracellulaires, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases'(2010), ANR-10-INBS-09-01/10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Bidault, Floran, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, and Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID

Subjects
MESH: Feedback, Physiological, [SDV]Life Sciences [q-bio], Gene Expression, LEGIONNAIRES-DISEASE, Electrophoretic Mobility Shift Assay, MESH: Legionnaires' Disease, Restriction Fragment Mapping, MESH: Base Sequence, MESH: Virulence, Pathology and Laboratory Medicine, MESH: Genome, Bacterial, Biochemistry, Pentose Phosphate Pathway, Tandem Mass Spectrometry, Medicine and Health Sciences, MESH: Bacterial Proteins, MESH: Evolution, Molecular, GENE-EXPRESSION, Oligonucleotide Array Sequence Analysis, Feedback, Physiological, MESH: Gene Expression Regulation, Bacterial, Virulence, Messenger RNA, GLYCOGEN BIOSYNTHESIS, Bacterial Pathogens, [SDV] Life Sciences [q-bio], Nucleic acids, Legionella Pneumophila, ESCHERICHIA-COLI, Medical Microbiology, MESH: Repressor Proteins, Host-Pathogen Interactions, MESH: Glycolysis, POSTTRANSCRIPTIONAL REGULATION, Legionnaires' Disease, Pathogens, MESSENGER-RNA, Glycolysis, Protein Binding, Research Article, MESH: Operon, MESH: Mutation, lcsh:QH426-470, DNA transcription, AUTOINDUCER SYNTHASE LQSA, Legionella, INTRACELLULAR REPLICATION, Research and Analysis Methods, Biosynthesis, Microbiology, Evolution, Molecular, MESH: Gene Expression Profiling, TRANSCRIPTION TERMINATION, Bacterial Proteins, Gene Types, Operon, Genetics, Humans, MESH: Protein Binding, MESH: Blotting, Northern, Gene Regulation, RNA, Messenger, Molecular Biology Techniques, Operons, PATHOGEN-HOST INTERACTIONS, Microbial Pathogens, Molecular Biology, MESH: Pentose Phosphate Pathway, MESH: RNA, Messenger, MESH: Humans, Base Sequence, Bacteria, Gene Expression Profiling, Gene Mapping, MESH: Host-Pathogen Interactions, Organisms, Biology and Life Sciences, MESH: Tandem Mass Spectrometry, Gene Expression Regulation, Bacterial, DNA, Blotting, Northern, MESH: Legionella pneumophila, Repressor Proteins, lcsh:Genetics, Riboswitch, Mutation, MESH: Oligonucleotide Array Sequence Analysis, Regulator Genes, RNA, Genome, Bacterial, MESH: Riboswitch
Abstract

The carbon storage regulator protein CsrA regulates cellular processes post-transcriptionally by binding to target-RNAs altering translation efficiency and/or their stability. Here we identified and analyzed the direct targets of CsrA in the human pathogen Legionella pneumophila. Genome wide transcriptome, proteome and RNA co-immunoprecipitation followed by deep sequencing of a wild type and a csrA mutant strain identified 479 RNAs with potential CsrA interaction sites located in the untranslated and/or coding regions of mRNAs or of known non-coding sRNAs. Further analyses revealed that CsrA exhibits a dual regulatory role in virulence as it affects the expression of the regulators FleQ, LqsR, LetE and RpoS but it also directly regulates the timely expression of over 40 Dot/Icm substrates. CsrA controls its own expression and the stringent response through a regulatory feedback loop as evidenced by its binding to RelA-mRNA and links it to quorum sensing and motility. CsrA is a central player in the carbon, amino acid, fatty acid metabolism and energy transfer and directly affects the biosynthesis of cofactors, vitamins and secondary metabolites. We describe the first L. pneumophila riboswitch, a thiamine pyrophosphate riboswitch whose regulatory impact is fine-tuned by CsrA, and identified a unique regulatory mode of CsrA, the active stabilization of RNA anti-terminator conformations inside a coding sequence preventing Rho-dependent termination of the gap operon through transcriptional polarity effects. This allows L. pneumophila to regulate the pentose phosphate pathway and the glycolysis combined or individually although they share genes in a single operon. Thus the L. pneumophila genome has evolved to acclimate at least five different modes of regulation by CsrA giving it a truly unique position in its life cycle., Author summary The RNA binding protein CsrA is the master regulator of the bi-phasic life cycle of Legionella pneumophila governing virulence expression in this intracellular pathogen. Here, we have used deep sequencing of RNA enriched by co-immunoprecipitation with epitope-tagged CsrA to identify CsrA-associated transcripts at the genome level. We found 479 mRNAs or non-coding RNAs to be targets of CsrA. Among those major regulators including FleQ, the regulator of flagella expression, LqsR, the regulator of quorum sensing and RpoS implicated in stress response were identified. The expression of over 40 type IV secreted effector proteins important for intracellular survival and virulence are under the control of CsrA. Combined with transcriptomics, whole shotgun proteomics of a wild type and a CsrA mutant strain and functional analyses of several CsrA-targeted RNAs we identified the first riboswitch in L. pneumophila, a thiamine pyrophosphate riboswitch, and discovered a new mode of regulation by CsrA that allows L. pneumophila to regulate the pentose phosphate pathway and the glycolysis combined or individually although they share genes in a single operon. Our results further underline the indispensable role of CsrA in the life cycle of L. pneumophila and provide new insights into its regulatory roles and mechanisms.

Published
2017

4. The endocannabinoid system controls food intake via olfactory processes

Author

Hans-Christian Pape, Theresa Wiesner, Hirac Gurden, Anna Chiarlone, Aya Wadleigh, Pierre-Marie Lledo, Luigi Bellocchio, Guillaume Ferreira, Federico Massa, Danièle Verrier, Claire Martin, Manuel Guzmán, Peggy Vincent, Tiffany Desprez, Gabriel Lepousez, Astrid Cannich, Leire Reguero, Beat Lutz, Pedro Grandes, Sabine Ruehle, Antoine Nissant, Giovanni Marsicano, Mounir Bendahmane, Floor Remmers, Edgar Soria-Gomez, Isabelle Matias, Carmelo Quarta, Physiopathologie du système nerveux central - Institut François Magendie, Université Bordeaux Segalen - Bordeaux 2-IFR8-Institut National de la Santé et de la Recherche Médicale (INSERM), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), Perception et Mémoire / Perception and Memory, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Imagerie et Modélisation en Neurobiologie et Cancérologie (IMNC (UMR_8165)), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), University of Bologna/Università di Bologna, Nutrition et Neurobiologie intégrée (NutriNeuro), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1 (UB)-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique, This work was supported by INSERM (G.M.), EU-Fp7 (REPROBESITY, HEALTH-F2-2008-223713, G.M.), European Research Council (ENDOFOOD, ERC-2010-StG-260515, G.M.), Fondation pour la Recherche Medicale (FRM-DRM-20101220445, G.M.), Region Aquitaine (G.M.), LABEX BRAIN (ANR-10-LABX-43), Fyssen Foundation (E.S.-G.), EMBO Post-doc Fellowship (L.B.), RTA, I.S. Carlos III (RD12/0028/0004, P.G.), Basque Country Government BCG IT764-13 (P.G.), University of the Basque Country UFI11/41 (P.G.), MINECO BFU2012-33334 (P.G.), Postdoctoral Specialization Contract from the University of the Basque Country UPV/EHU (L.R.), MINECO SAF2012-35759 (M.G.), Deutsche Forschungsgemeinschaft (SFB-TRR 58, B.L. and H.-C.P.), CONACyT (E.S.-G.). The Lledo laboratory is part of the École des Neurosciences de Paris Ile-de-France network, a member of the Bio-Psy Labex and is supported partially by 'AG2R-La-Mondiale'., We thank D. Gonzales, N. Aubailly and all of the personnel of the Animal Facility of the NeuroCentre Magendie for mouse care and genotyping, A. Desprez for help with the odor task set-up, D. Herrera and S. Rahayel (NutriBrain School 2012) for help with some experiments, all of the members of the Marsicano laboratory for useful discussions, A. Bacci, D. Cota, V. Deroche and M. Valley for critically reading the manuscript, and K. Deisseroth (Stanford University) and B.L. Roth (University of North Carolina) for providing the plasmids coding for ChR2 and DREADD, respectively., ANR-10-IDEX-0003,IDEX BORDEAUX,Initiative d'excellence de l'Université de Bordeaux(2010), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), European Project: 223713,EC:FP7:HEALTH,FP7-HEALTH-2007-B,REPROBESITY(2008), European Project: 260515,EC:FP7:ERC,ERC-2010-StG_20091118,ENDOFOOD(2011), CIBER de Enfermedades Neurodegenerativas (CIBERNED), Complutense University of Madrid (UCM), University of the Basque Country [Bizkaia] (UPV/EHU), Perception et Mémoire, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Johannes Gutenberg - University of Mainz (JGU), Westfälische Wilhelms-Universität Münster (WWU), University of Bologna, Nutrition et Neurobiologie intégrée (NutriNeur0), Ecole nationale supérieure de chimie, biologie et physique-Institut Polytechnique de Bordeaux-Université Sciences et Technologies - Bordeaux 1-Institut National de la Recherche Agronomique (INRA)-Université Bordeaux Segalen - Bordeaux 2, ANR-10-IDEX-03-02/10-LABX-0043,BRAIN,Bordeaux Region Aquitaine Initiative for Neuroscience(2010), ANR-11-IDEX-0004-02/11-LABX-0035,BIOPSY,Laboratoire de Psychiatrie Biologique(2011), Johannes Gutenberg - Universität Mainz (JGU), and Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique

Subjects
Male, Olfactory system, MESH: Olfactory Perception, Cannabinoid receptor, MESH: Feedback, Physiological, [SDV]Life Sciences [q-bio], medicine.medical_treatment, MESH: Cannabinoid Receptor Agonists, MESH: Endocannabinoids, MESH: Receptor, Cannabinoid, CB1, Synaptic Transmission, MESH: Mice, Knockout, MESH: Eating, Eating, Mice, Olfactory bulb, Receptor, Cannabinoid, CB1, MESH: Animals, Feedback, Physiological, Mice, Knockout, musculoskeletal, neural, and ocular physiology, General Neuroscience, digestive, oral, and skin physiology, Olfactory Pathways, Endocannabinoid system, MESH: Feeding Behavior, lipids (amino acids, peptides, and proteins), psychological phenomena and processes, MESH: Olfactory Bulb, Biology, Inhibitory postsynaptic potential, Glutamatergic, MESH: Mice, Inbred C57BL, MESH: Synaptic Transmission, medicine, Animals, MESH: Mice, Cannabinoid Receptor Agonists, Feeding Behavior, Olfactory Perception, MESH: Male, Mice, Inbred C57BL, nervous system, Odor, Feeding behaviour, Cannabinoid, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Neuroscience, MESH: Olfactory Pathways, Endocannabinoids
Abstract

Comment in Sensory systems: the hungry sense. [Nat Rev Neurosci. 2014] Inhaling: endocannabinoids and food intake. [Nat Neurosci. 2014]; International audience; Hunger arouses sensory perception, eventually leading to an increase in food intake, but the underlying mechanisms remain poorly understood. We found that cannabinoid type-1 (CB1) receptors promote food intake in fasted mice by increasing odor detection. CB1 receptors were abundantly expressed on axon terminals of centrifugal cortical glutamatergic neurons that project to inhibitory granule cells of the main olfactory bulb (MOB). Local pharmacological and genetic manipulations revealed that endocannabinoids and exogenous cannabinoids increased odor detection and food intake in fasted mice by decreasing excitatory drive from olfactory cortex areas to the MOB. Consistently, cannabinoid agonists dampened in vivo optogenetically stimulated excitatory transmission in the same circuit. Our data indicate that cortical feedback projections to the MOB crucially regulate food intake via CB1 receptor signaling, linking the feeling of hunger to stronger odor processing. Thus, CB1 receptor-dependent control of cortical feedback projections in olfactory circuits couples internal states to perception and behavior.

Published
2014

5. A Feedforward Regulatory Loop between HuR and the Long Noncoding RNA linc-MD1 Controls Early Phases of Myogenesis

Author

Ivano Legnini, Irene Bozzoni, Mariangela Morlando, Alessandro Fatica, Arianna Mangiavacchi, Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia (IIT), Department of Biology and Biotechnology 'Charles Darwin', Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Réseau International des Instituts Pasteur (RIIP), and This work was partially supported by grants from Telethon (GGP11149), Epigen, Parent Project Italia, AIRC, IIT 'SEED,' FIRB, and PRIN.

Subjects
MESH: Cell Differentiation, Cytoplasm, MESH: Feedback, Physiological, Physiological, Cellular differentiation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Muscle Development, Feedback, hur, long non coding rna, micro rna, Cell Line, Mice, Short Article, Animals, Cell Differentiation, ELAV Proteins, Feedback, Physiological, MicroRNAs, RNA, Long Noncoding, microRNA, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Molecular Biology, Drosha, Genetics, Myogenesis, MESH: Cytoplasm, MESH: Hu Paraneoplastic Encephalomyelitis Antigens, RNA, Cell Biology, Long non-coding RNA, MESH: Cell Line, MESH: RNA, Long Noncoding, MESH: Muscle Development, Long Noncoding, MESH: MicroRNAs, Biogenesis
Abstract

Summary The muscle-specific long noncoding RNA linc-MD1 was shown to be expressed during early phases of muscle differentiation and to trigger the switch to later stages by acting as a sponge for miR-133 and miR-135. Notably, linc-MD1 is also the host transcript of miR-133b, and their biogenesis is mutually exclusive. Here, we describe that this alternative synthesis is controlled by the HuR protein, which favors linc-MD1 accumulation through its ability to bind linc-MD1 and repress Drosha cleavage. We show that HuR is under the repressive control of miR-133 and that the sponging activity of linc-MD1 consolidates HuR expression in a feedforward positive loop. Finally, we show that HuR also acts in the cytoplasm, reinforcing linc-MD1 sponge activity by cooperating for miRNA recruitment. An increase in miR-133 synthesis, mainly from the two unrelated miR-133a coding genomic loci, is likely to trigger the exit from this circuitry and progression to later differentiation stages., Graphical Abstract, Highlights • A feedforward positive loop exists between linc-MD1 and HuR during myogenesis • HuR controls the relative biogenesis of miR-133b and its host linc-MD1 RNA • Linc-MD1, by sponging miR-133, alleviates its repression on HuR expression • Cytoplasmic HuR reinforces linc-MD1 activity by cooperating for miRNA recruitment, linc-MD1 and miR-133 are alternatively processed from the same precursor RNA. These RNAs play opposing roles in early phases of myogenesis. Legnini et al. now show that the balance between the RNAs is regulated by HuR, which inhibits generation of miR-133 by inhibiting microprocessor activity on the precursor RNA.

Published
2014

6. A blue-light photoreceptor mediates the feedback regulation of photosynthesis

Author

Leonardo Magneschi, Shinichiro Maruyama, Jun Minagawa, Maria Mittag, Andre Greiner, Peter Hegemann, Tilman Kottke, Serena Flori, Loic Cusant, Dimitris Petroutsos, Ryutaro Tokutsu, Giovanni Finazzi, Physiologie cellulaire et végétale (LPCV), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Division of Environmental Photobiology, National Institute for Basic Biology [Okazaki], Tohoku University [Sendai], Humboldt State University (HSU), Institute for Plant Biochemistry and Biotechnology, Westfälische Wilhelms-Universität Münster (WWU), Physical and Biophysical Chemistry, Institut für Allgemeine Botanik und Pflanzenphysiologie, Friedrich-Schiller-Universität Jena, Marie Curie Initial Training Network Accliphot (FP7-PEOPLE-2012-ITN), CNRS Défi (ENRS 2013), CEA Bioénergies program, HFSP (HFSP0052), NIBB Cooperative Research Program for the Okazaki Large Spectrograph, JSPS KAKENHI (JP15H05599, JP26251033 and JP16H06553), NEDO (P07015), MEXT (through the Network of Centres of Carbon Dioxide Resource Studies in Plants, German Research Foundation, DFG, grants FOR1261, ANR-12-BIME-0005,DiaDomOil,Domestication des diatomées pour la production de biocarburants(2012), ANR-10- LABX-49-01,Labex GRAL,Labex GRAL, Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany], ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), and Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)

Subjects
0106 biological sciences, 0301 basic medicine, MESH: Chlamydomonas reinhardtii, Phototropins, Light Signal Transduction, Phototropin, MESH: Light-Harvesting Protein Complexes, Light, Algae, Cell Survival, MESH: Feedback, Physiological, Acclimatization, Light-Harvesting Protein Complexes, Color, Phot, MESH: Acclimatization, Biology, Photochemistry, 01 natural sciences, 03 medical and health sciences, Cryptochrome, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Photosynthesis, MESH: Protein Kinases, MESH: Photosynthesis, MESH: Color, Feedback, Physiological, Multidisciplinary, Photoreceptor, MESH: Phototropins, Phytochrome, Photoprotection, Non-photochemical quenching, MESH: Photosystem II Protein Complex, Photosystem II Protein Complex, MESH: Light Signal Transduction, MESH: Light, Light intensity, 030104 developmental biology, MESH: Cell Survival, Light acclimation, Biophysics, Energy source, Protein Kinases, Chlamydomonas reinhardtii, 010606 plant biology & botany
Abstract

International audience; In plants and algae, light serves both as the energy source for photosynthesis and a biological signal that triggers cellular responses via specific sensory photoreceptors. Red light is perceived by bilin-containing phytochromes and blue light by the flavin-containing cryptochromes and/or phototropins (PHOTs), the latter containing two photosensory light, oxygen, or voltage (LOV) domains. Photoperception spans several orders of light intensity, ranging from far below the threshold for photosynthesis to values beyond the capacity of photosynthetic CO2 assimilation. Excess light may cause oxidative damage and cell death, processes prevented by enhanced thermal dissipation via high-energy quenching (qE), a key photoprotective response. Here we show the existence of a molecular link between photoreception, photosynthesis, and photoprotection in the green alga Chlamydomonas reinhardtii. We show that PHOT controls qE by inducing the expression of the qE effector protein LHCSR3 (light-harvesting complex stress-related protein 3) in high light intensities. This control requires blue-light perception by LOV domains on PHOT, LHCSR3 induction through PHOT kinase, and light dissipation in photosystem II via LHCSR3. Mutants deficient in the PHOT gene display severely reduced fitness under excessive light conditions, indicating that the sensing, utilization, and dissipation of light is a concerted process that plays a vital role in microalgal acclimation to environments of variable light intensities.

Published
2016

7. Kinetic Studies of the Arf Activator Arno on Model Membranes in the Presence of Arf Effectors Suggest Control by a Positive Feedback Loop

Author

Catherine L. Jackson, Bruno Antonny, Romain Gautier, Danièle Stalder, Eric Macia, Hélène Barelli, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'enzymologie et biochimie structurales (LEBS), Centre National de la Recherche Scientifique (CNRS), and Ministère de l'Enseignement Supérieur et de la Recherche, Agence Nationale de la Recherche Grant ANR-08-BLAN-0060-01

Subjects
MESH: ADP-Ribosylation Factors, GTPase-activating protein, GTP', ADP ribosylation factor, MESH: Feedback, Physiological, G protein, Retinal Pigment Epithelium, MESH: GTPase-Activating Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Guanosine triphosphate, Transfection, Biochemistry, Cell Line, MESH: Protein Structure, Tertiary, 03 medical and health sciences, chemistry.chemical_compound, Guanine Nucleotide Exchange Factors, Humans, MESH: Guanine Nucleotide Exchange Factors, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Phosphatidylinositol, Molecular Biology, 030304 developmental biology, Feedback, Physiological, 0303 health sciences, MESH: Guanosine Triphosphate, MESH: Humans, MESH: Kinetics, ADP-Ribosylation Factors, Chemistry, MESH: ADP-Ribosylation Factor 1, MESH: Transfection, GTPase-Activating Proteins, 030302 biochemistry & molecular biology, Cell Biology, MESH: Retinal Pigment Epithelium, Protein Structure, Tertiary, MESH: Cell Line, Cell biology, Pleckstrin homology domain, Kinetics, ADP-Ribosylation Factor 6, Liposomes, MESH: Liposomes, ADP-Ribosylation Factor 1, Guanosine Triphosphate, Guanine nucleotide exchange factor, Signal Transduction
Abstract

International audience; Proteins of the cytohesin/Arno/Grp1 family of Arf activators are positive regulators of the insulin-signaling pathway and control various remodeling events at the plasma membrane. Arno has a catalytic Sec7 domain, which promotes GDP to GTP exchange on Arf, followed by a pleckstrin homology (PH) domain. Previous studies have revealed two functions of the PH domain: inhibition of the Sec7 domain and membrane targeting. Interestingly, the Arno PH domain interacts not only with a phosphoinositide (phosphatidylinositol 4,5-bisphosphate or phosphatidylinositol 3,4,5-trisphosphate) but also with an activating Arf family member, such as Arf6 or Arl4. Using the full-length membrane-bound forms of Arf1 and Arf6 instead of soluble forms, we show here that the membrane environment dramatically affects the mechanism of Arno activation. First, Arf6-GTP stimulates Arno at nanomolar concentrations on liposomes compared with micromolar concentrations in solution. Second, mutations in the PH domain that abolish interaction with Arf6-GTP render Arno completely inactive when exchange reactions are reconstituted on liposomes but have no effect on Arno activity in solution. Third, Arno is activated by its own product Arf1-GTP in addition to a distinct activating Arf isoform. Consequently, Arno activity is strongly modulated by competition with Arf effectors. These results show that Arno behaves as a bistable switch, having an absolute requirement for activation by an Arf protein but, once triggered, becoming highly active through the positive feedback effect of Arf1-GTP. This property of Arno might provide an explanation for its function in signaling pathways that, once triggered, must move forward decisively.

Published
2011

8. EFD Is an ERF Transcription Factor Involved in the Control of Nodule Number and Differentiation inMedicago truncatula

Author

Françoise de Billy, Andreas Niebel, Tatiana Vernié, Christian Rogers, Florian Frugier, Giles E. D. Oldroyd, Julie Plet, Jean-Philippe Combier, Pascal Gamas, Sandra Moreau, Laboratoire des interactions plantes micro-organismes ( LIPMO ), Institut National de la Recherche Agronomique ( INRA ) -Centre National de la Recherche Scientifique ( CNRS ), Ecologie microbienne ( EM ), Centre National de la Recherche Scientifique ( CNRS ) -Ecole Nationale Vétérinaire de Lyon ( ENVL ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique ( INRA ) -VetAgro Sup ( VAS ), Institut des sciences du végétal ( ISV ), Centre National de la Recherche Scientifique ( CNRS ), Laboratoire des interactions plantes micro-organismes (LIPM), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Ecologie Microbienne - UMR 5557 (LEM), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Ecole Nationale Vétérinaire de Lyon (ENVL), Institut des sciences du végétal (ISV), Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Lyon (ENVL)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)

Subjects
MESH: Signal Transduction, 0106 biological sciences, [ SDV.BV ] Life Sciences [q-bio]/Vegetal Biology, Cytokinins, MESH : Molecular Sequence Data, MESH : Transcription Factors, MESH: Feedback, Physiological, Regulator, MESH : Gene Deletion, Plant Science, Plant Root Nodulation, 01 natural sciences, Nod factor, chemistry.chemical_compound, MESH : Nitrogen Fixation, MESH: Phylogeny, MESH: Medicago truncatula, Research Articles, Phylogeny, Plant Proteins, Regulator gene, Feedback, Physiological, MESH : Cell Nucleus, 0303 health sciences, MESH: Plant Proteins, food and beverages, MESH: Transcription Factors, MESH : Feedback, Physiological, MESH : Cytokinins, Medicago truncatula, Cell biology, MESH: Root Nodules, Plant, Multigene Family, Cytokinin, RNA Interference, MESH: Cytokinins, Root Nodules, Plant, MESH: Plant Root Nodulation, Signal Transduction, MESH: Cell Nucleus, MESH: Ethylenes, Molecular Sequence Data, MESH: RNA Interference, MESH : Multigene Family, Biology, MESH: Nitrogen Fixation, MESH: Gene Expression Profiling, MESH : Root Nodules, Plant, 03 medical and health sciences, Nitrogen Fixation, MESH : Plant Proteins, Botany, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Transcription factor, 030304 developmental biology, Cell Nucleus, MESH : Signal Transduction, MESH: Molecular Sequence Data, Gene Expression Profiling, MESH : Gene Expression Profiling, MESH : Medicago truncatula, fungi, MESH : Phylogeny, MESH : Sinorhizobium meliloti, Cell Biology, Ethylenes, Meristem, biology.organism_classification, Response regulator, chemistry, MESH: Gene Deletion, MESH: Multigene Family, MESH : RNA Interference, MESH: Sinorhizobium meliloti, MESH : Plant Root Nodulation, Gene Deletion, MESH : Ethylenes, Sinorhizobium meliloti, Transcription Factors, 010606 plant biology & botany
Abstract

Mechanisms regulating legume root nodule development are still poorly understood, and very few regulatory genes have been cloned and characterized. Here, we describe EFD (for ethylene response factor required for nodule differentiation), a gene that is upregulated during nodulation in Medicago truncatula. The EFD transcription factor belongs to the ethylene response factor (ERF) group V, which contains ERN1, 2, and 3, three ERFs involved in Nod factor signaling. The role of EFD in the regulation of nodulation was examined through the characterization of a null deletion mutant (efd-1), RNA interference, and overexpression studies. These studies revealed that EFD is a negative regulator of root nodulation and infection by Rhizobium and that EFD is required for the formation of functional nitrogen-fixing nodules. EFD appears to be involved in the plant and bacteroid differentiation processes taking place beneath the nodule meristem. We also showed that EFD activated Mt RR4, a cytokinin primary response gene that encodes a type-A response regulator. We propose that EFD induction of Mt RR4 leads to the inhibition of cytokinin signaling, with two consequences: the suppression of new nodule initiation and the activation of differentiation as cells leave the nodule meristem. Our work thus reveals a key regulator linking early and late stages of nodulation and suggests that the regulation of the cytokinin pathway is important both for nodule initiation and development.

Published
2008

9. A self-organizing miR-132/Ctbp2 circuit regulates bimodal notch signals and glial progenitor fate choice during spinal cord maturation

Author

Laure Bally-Cuif, Bart De Strooper, Pierre Lau, Evgenia Salta, Carlo Sala Frigerio, Marion Coolen, Center for the Biology of Disease, and KU Leuven (VIB), Neurobiologie et Développement (N&eD), Centre National de la Recherche Scientifique (CNRS), Institut de Neurobiologie Alfred Fessard (INAF), and NMR Research Unit, Institute of Neurology, University College London

Subjects
MESH: Cell Differentiation, MESH: Neural Stem Cells, MESH: Feedback, Physiological, Notch signaling pathway, MESH: Zebrafish Proteins, Biology, General Biochemistry, Genetics and Molecular Biology, MESH: Spinal Cord, miR-132, Neural Stem Cells, Sirtuin 1, MESH: Gene Expression Regulation, Developmental, medicine, Animals, MESH: Animals, Progenitor cell, MESH: Sirtuin 1, Eye Proteins, MESH: Zebrafish, Molecular Biology, Zebrafish, Progenitor, Feedback, Physiological, Receptors, Notch, Gene Expression Regulation, Developmental, Cell Differentiation, Cell Biology, Anatomy, Zebrafish Proteins, biology.organism_classification, Spinal cord, Embryonic stem cell, CTBP2, Cell biology, Repressor Proteins, MESH: Microglia, MicroRNAs, medicine.anatomical_structure, Spinal Cord, MESH: Repressor Proteins, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Microglia, MESH: Receptors, Notch, MESH: MicroRNAs, Developmental Biology
Abstract

International audience; Radial glial progenitors play pivotal roles in the development and patterning of the spinal cord, and their fate is controlled by Notch signaling. How Notch is shaped to regulate their crucial transition from expansion toward differentiation remains, however, unknown. miR-132 in the developing zebrafish dampens Notch signaling via a cascade involving the transcriptional corepressor Ctbp2 and the Notch suppressor Sirt1. At early embryonic stages, high Ctbp2 levels sustain Notch signaling and radial glial expansion and concomitantly induce miR-132 expression via a double-negative feedback loop involving Rest inhibition. The changing balance in miR-132 and Ctbp2 interaction gradually drives the switch in Notch output and radial glial progenitor fate as part of the larger developmental program involved in the transition from embryonic to larval spinal cord.

Published
2014

10. The late news on baff in autoimmune diseases

Author

Pierre Youinou, Jacques-Olivier Pers, Michel, Geneviève, Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Laboratoire d'Immunologie et Immunothérapie, and Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)

Subjects
[SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Feedback, Physiological, medicine.medical_treatment, Immunology, Autoimmunity, MESH: Protein Isoforms, Biology, Autoimmune Diseases, 03 medical and health sciences, 0302 clinical medicine, stomatognathic system, immune system diseases, B cell homeostasis, MESH: Autoimmune Diseases, MESH: B-Lymphocytes, hemic and lymphatic diseases, MESH: Autoimmunity, B-Cell Activating Factor, medicine, Animals, Homeostasis, Humans, Protein Isoforms, Immunology and Allergy, MESH: Animals, MESH: B-Cell Activating Factor, skin and connective tissue diseases, B-cell activating factor, Overproduction, 030304 developmental biology, Feedback, Physiological, B-Lymphocytes, 0303 health sciences, MESH: Humans, MESH: Alternative Splicing, 3. Good health, Alternative Splicing, stomatognathic diseases, Cytokine, MESH: Homeostasis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Splice isoforms, 030215 immunology
Abstract

International audience; The B cell-activating factor of the tumor-necrosis factor family (BAFF) plays a dominant role in the B cell homeostasis. By rescuing autoreactive B cells, excessive BAFF favors the development of autoimmune diseases. Given the numbers of variants of this B cell-specific cytokine, caution must be exercized when determining its serum level. Alternate splice isoforms, such as Δ3 BAFF and Δ4 BAFF, have been identified. They raise the possibility that their overproduction impact the synthesis of full-length BAFF.

Published
2010

11. Loss of a Negative Feedback Loop Involving Pea3 and Cyclin D2 Is Required for Pea3-Induced Migration in Transformed Mammary Epithelial Cells

Author

Zoulika Kherrouche, Isabelle Damour, Patrick Dumont, Franck Ladam, David Tulasne, Anne Chotteau-Lelievre, Yvan de Launoit, Mécanismes de tumorigenèse et thérapies ciblées, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), This work was supported by the CNRS, the Institut Pasteur de Lille and INSERM, and by grants from the 'Ligue contre le Cancer, comité Aisne,' and the 'Association pour la Recherche sur le Cancer.', and The authors thank the Microscopy-Imaging-Cytometry Facility of the Lille Pasteur Campus (MICPal) and the BioImaging Center Lille Nord-de-France for access to instruments and technical advice.

Subjects
Cancer Research, MESH: Feedback, Physiological, Cyclin D, [SDV]Life Sciences [q-bio], Cyclin A, Cyclin B, Mice, SCID, medicine.disease_cause, Cell morphology, Mice, 0302 clinical medicine, MESH: Mammary Glands, Animal/pathology, Cell Movement, Cyclin D2, MESH: Animals, MESH: Mice, SCID, ComputingMilieux_MISCELLANEOUS, Feedback, Physiological, 0303 health sciences, MESH: Transcription Factors/metabolism, biology, MESH: Mammary Neoplasms, Experimental/genetics, MESH: Transforming Growth Factor beta1/metabolism, Cell migration, MESH: Gene Expression Regulation, Neoplastic, Cell biology, Gene Expression Regulation, Neoplastic, MESH: Epithelial Cells/metabolism, Cell Transformation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, MESH: HEK293 Cells, MESH: Mammary Neoplasms, Experimental/pathology, Female, MESH: Xenograft Model Antitumor Assays, Epithelial-Mesenchymal Transition, MESH: Cell Line, Tumor, MESH: Mammary Glands, Animal/metabolism, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Mammary Neoplasms, Experimental/metabolism, Transforming Growth Factor beta1, 03 medical and health sciences, Mammary Glands, Animal, Cell Line, Tumor, MESH: Cell Proliferation, medicine, Animals, Humans, Neoplasm Invasiveness, Molecular Biology, MESH: Mice, Cell Proliferation, 030304 developmental biology, MESH: Humans, MESH: Epithelial Cells/pathology, Mammary Neoplasms, Experimental, Epithelial Cells, MESH: Neoplasm Invasiveness, Xenograft Model Antitumor Assays, body regions, HEK293 Cells, MESH: Cell Transformation, Neoplastic, MESH: Epithelial-Mesenchymal Transition, MESH: Cell Movement/genetics, biology.protein, Cancer research, MESH: Cyclin D2/metabolism, Carcinogenesis, MESH: Female, Cyclin A2, Transcription Factors
Abstract

The Ets family transcription factor Pea3 (ETV4) is involved in tumorigenesis especially during the metastatic process. Pea3 is known to induce migration and invasion in mammary epithelial cell model systems. However, the molecular pathways regulated by Pea3 are still misunderstood. In the current study, using in vivo and in vitro assays, Pea3 increased the morphogenetic and tumorigenic capacity of mammary epithelial cells by modulating their cell morphology, proliferation, and migration potential. In addition, Pea3 overexpression favored an epithelial–mesenchymal transition (EMT) triggered by TGF-β1. During investigation for molecular events downstream of Pea3, Cyclin D2 (CCND2) was identified as a new Pea3 target gene involved in the control of cellular proliferation and migration, a finding that highlights a new negative regulatory loop between Pea3 and Cyclin D2. Furthermore, Cyclin D2 expression was lost during TGF-β1–induced EMT and Pea3-induced tumorigenesis. Finally, restored Cyclin D2 expression in Pea3-dependent mammary tumorigenic cells decreased cell migration in an opposite manner to Pea3. As such, these data demonstrate that loss of the negative feedback loop between Cyclin D2 and Pea3 contributes to Pea3-induced tumorigenesis. Implications: This study reveals molecular insight into how the Ets family transcription factor Pea3 favors EMT and contributes to tumorigenesis via a negative regulatory loop with Cyclin D2, a new Pea3 target gene. Mol Cancer Res; 11(11); 1412–24. ©2013 AACR.

Published
2013

12. Type I interferon potentiates T-cell receptor mediated induction of IL-10-producing CD4 + T cells

Author

Corre, Béatrice, Perrier, Julie, El Khouri, Margueritte, Cerboni, Silvia, Pellegrini, Sandra, Michel, Frédérique, Signalisation des Cytokines, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), The study was supported by grants from the foundation ARSEP (Aide à la Recherche sur la Sclérose En Plaques), Institut Pasteur and Centre National pour la Recherche Scientifique (CNRS)., We thank Antonio Bandeira‐Ferreira and Paulo Vieira for critical reading of the manuscript and Valentina Libri for cell sorting at the Center of Human Immunology, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Cell Differentiation, MESH: Signal Transduction, MESH: Interleukin-10, MESH: Feedback, Physiological, MESH: Interferon-gamma, MESH: Receptor Cross-Talk, MESH: Inflammation Mediators, Receptors, Antigen, T-Cell, chemical and pharmacologic phenomena, MESH: T-Lymphocyte Subsets, Lymphocyte Activation, T-Lymphocytes, Regulatory, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Interferon-gamma, T helper cells, CD28 Antigens, T-Lymphocyte Subsets, MESH: Forkhead Transcription Factors, Humans, MESH: Protein Binding, MESH: Lymphocyte Activation, Cells, Cultured, Feedback, Physiological, MESH: CD28 Antigens, MESH: Humans, MESH: T-Lymphocytes, Regulatory, Tr1 cells, Interferon-alpha, Cell Differentiation, Forkhead Transcription Factors, MESH: Receptors, Antigen, T-Cell, Receptor Cross-Talk, CD4+ T cells, Interleukin-10, MESH: Leukocyte Common Antigens, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, IFN-α/β, IL-10, Leukocyte Common Antigens, Inflammation Mediators, MESH: Interferon-alpha, Protein Binding, Signal Transduction, MESH: Cells, Cultured
Abstract

International audience; Type I interferons (IFNs) have the dual ability to promote the development of the immune response and exert an anti-inflammatory activity. We analyzed the integrated effect of IFN-α, TCR signal strength, and CD28 costimulation on human CD4⁺ T-cell differentiation into cell subsets producing the anti- and proinflammatory cytokines IL-10 and IFN-γ. We show that IFN-α boosted TCR-induced IL-10 expression in activated peripheral CD45RA⁺CD4⁺ T cells and in whole blood cultures. The functional cooperation between TCR and IFN-α efficiently occurred at low engagement of receptors. Moreover, IFN-α rapidly cooperated with anti-CD3 stimulation alone. IFN-α, but not IL-10, drove the early development of type I regulatory T cells that were mostly IL-10⁺ Foxp3⁻ IFN-γ⁻ and favored IL-10 expression in a fraction of Foxp3⁺ T cells. Our data support a model in which IFN-α costimulates TCR toward the production of IL-10 whose level can be amplified via an autocrine feedback loop.

Published
2013

13. Gliotransmission and Brain Glucose Sensing: Critical Role of Endozepines

Author

Lanfray, Damien, Arthaud, Sébastien, Ouellet, Johanne, Compère, Vincent, Do Rego, Jean-Luc, Leprince, Jérôme, Lefranc, Benjamin, Castel, Hélène, Bouchard, Cynthia, Monge-Roffarello, Boris, Richard, Denis, Pelletier, Georges, Vaudry, Hubert, Tonon, Marie-Christine, Morin, Fabrice, Compere, V., Tonon, C., Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plate-Forme de Recherche en Imagerie Cellulaire de Haute-Normandie (PRIMACEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Henri Becquerel-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Logique, Algorithmique et Informatique (LLAIC1), Université d'Auvergne - Clermont-Ferrand I (UdA), Unité de Recherche en Génétique et Amélioration des Plantes (UR254), Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), CHU Rouen, Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-CRLCC Henri Becquerel-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Neuroendocrinologie cellulaire et moléculaire, Télécom SudParis (TSP), Airbus Defence and Space [Toulouse], Université Laval [Québec] (ULaval), Leprince, Jérôme, Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-High-tech Research Infrastructures for Life Sciences (HeRacLeS), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, MESH: Feedback, Physiological, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Appetite Stimulants, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Neuropeptides, Synaptic Transmission, MESH: Appetitive Behavior, MESH: Arcuate Nucleus of Hypothalamus, Tissue Culture Techniques, MESH: Appetite Depressants, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Animals, MESH: Nerve Tissue Proteins, MESH: Peptide Fragments, Diazepam Binding Inhibitor, Feedback, Physiological, Appetitive Behavior, MESH: Appetite Stimulants, Receptors, Melanocortin, MESH: Gene Expression Regulation, MESH: Glucose, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Neuroglia, MESH: Injections, Intraventricular, Neuroglia, Signal Transduction, MESH: Rats, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Hypothalamus, Nerve Tissue Proteins, Appetite Depressants, MESH: Synaptic Transmission, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Tissue Culture Techniques, Rats, Wistar, MESH: Receptors, Melanocortin, Injections, Intraventricular, Appetite Regulation, Neuropeptides, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Arcuate Nucleus of Hypothalamus, MESH: Rats, Wistar, MESH: Hypothalamus, MESH: Male, Peptide Fragments, Rats, Glucose, Gene Expression Regulation, MESH: Protein Processing, Post-Translational, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Diazepam Binding Inhibitor, Protein Processing, Post-Translational, MESH: Appetite Regulation
Abstract

International audience; Hypothalamic glucose sensing is involved in the control of feeding behavior and peripheral glucose homeostasis, and glial cells are suggested to play an important role in this process. Diazepam-binding inhibitor (DBI) and its processing product the octadecaneuropeptide (ODN), collectively named endozepines, are secreted by astroglia, and ODN is a potent anorexigenic factor. Therefore, we investigated the involvement of endozepines in brain glucose sensing. First, we showed that intracerebroventricular administration of glucose in rats increases DBI expression in hypothalamic glial-like tanycytes. We then demonstrated that glucose stimulates endozepine secretion from hypothalamic explants. Feeding experiments indicate that the anorexigenic effect of central administration of glucose was blunted by coinjection of an ODN antagonist. Conversely, the hyperphagic response elicited by central glucoprivation was suppressed by an ODN agonist. The anorexigenic effects of centrally injected glucose or ODN agonist were suppressed by blockade of the melanocortin-3/4 receptors, suggesting that glucose sensing involves endozepinergic control of the melanocortin pathway. Finally, we found that brain endozepines modulate blood glucose levels, suggesting their involvement in a feedback loop controlling whole-body glucose homeostasis. Collectively, these data indicate that endozepines are a critical relay in brain glucose sensing and potentially new targets in treatment of metabolic disorders.

Published
2013

14. Identification of the Rps28 binding motif from yeast Edc3 involved in the autoregulatory feedback loop controlling RPS28B mRNA decay

Author

Bertrand Séraphin, Olga Kolesnikova, Régis Back, Marc Graille, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biochimie de l'Ecole polytechnique (BIOC), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Structurale de la Cellule (BIOC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de biochimie et biophysique moléculaire et cellulaire (IBBMC), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), and Roura, Denis

Subjects
Ribosomal Proteins, Riboswitch, Saccharomyces cerevisiae Proteins, MESH: Feedback, Physiological, RNA Stability, Molecular Sequence Data, Saccharomyces cerevisiae, MESH: Amino Acid Sequence, Biology, 03 medical and health sciences, MESH: Saccharomyces cerevisiae Proteins, 0302 clinical medicine, Ribosomal protein, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, Protein Interaction Domains and Motifs, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, RNA, Messenger, Binding site, Conserved Sequence, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, MESH: RNA, Messenger, 030304 developmental biology, Feedback, Physiological, MESH: Protein Interaction Domains and Motifs, 0303 health sciences, Binding Sites, MESH: Conserved Sequence, MESH: Molecular Sequence Data, RNA, MESH: RNA Stability, MESH: Ribosomal Proteins, biology.organism_classification, Cell biology, Saccharomycetaceae, MESH: Binding Sites, eIF4A, Sequence motif, 030217 neurology & neurosurgery
Abstract

International audience; In the yeast Saccharomyces cerevisiae, the Edc3 protein was previously reported to participate in the auto-regulatory feedback loop controlling the level of the RPS28B messenger RNA (mRNA). We show here that Edc3 binds directly and tightly to the globular core of Rps28 ribosomal protein. This binding occurs through a motif that is present exclusively in Edc3 proteins from yeast belonging to the Saccharomycetaceae phylum. Functional analyses indicate that the ability of Edc3 to interact with Rps28 is not required for its general function and for its role in the regulation of the YRA1 pre-mRNA decay. In contrast, this interaction appears to be exclusively required for the auto-regulatory mechanism controlling the RPS28B mRNA decay. These observations suggest a plausible model for the evolutionary appearance of a Rps28 binding motif in Edc3.

Published
2013

15. Modelling Erythroblastic Islands: Using a Hybrid Model to Assess the Function of Central Macrophage

Author

Polina Kurbatova, Olivier Gandrillon, Nikolai Bessonov, Stephan Fischer, Fabien Crauste, Vitaly Volpert, COMputational BIology and data miNING (COMBINING), Laboratoire d'InfoRmatique en Image et Systèmes d'information (LIRIS), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École Centrale de Lyon (ECL), Université de Lyon-Université Lumière - Lyon 2 (UL2)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Université Lumière - Lyon 2 (UL2)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Multi-scale modelling of cell dynamics : application to hematopoiesis (DRACULA), Institut Camille Jordan [Villeurbanne] (ICJ), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institute of Mechanical Engineering Problems [St. Petersburg] (IPME), Russian Academy of Sciences [Moscow] (RAS), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), ANR-09-JCJC-0100,ProCell(2009), Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut Camille Jordan (ICJ), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), and Institut Camille Jordan (ICJ)

Subjects
Erythroblasts, Macrophage, MESH: Feedback, Physiological, medicine.medical_treatment, Cell Communication, Quantitative Biology - Quantitative Methods, 0302 clinical medicine, Cell Behavior (q-bio.CB), Erythropoiesis, MESH: Erythroblasts, Quantitative Methods (q-bio.QM), Erythroblastic islands, Feedback, Physiological, 0303 health sciences, MESH: Bone Marrow Cells, Applied Mathematics, General Medicine, Cell biology, medicine.anatomical_structure, Biological Physics (physics.bio-ph), 030220 oncology & carcinogenesis, Modeling and Simulation, General Agricultural and Biological Sciences, Intracellular, Hybrid model, Statistics and Probability, FOS: Physical sciences, Bone Marrow Cells, Biology, Models, Biological, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, MESH: Cell Communication, medicine, Extracellular, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Physics - Biological Physics, Progenitor cell, 030304 developmental biology, MESH: Humans, General Immunology and Microbiology, Macrophages, Growth factor, MESH: Erythropoiesis, MESH: Models, Biological, MESH: Macrophages, Spindle apparatus, FOS: Biological sciences, Quantitative Biology - Cell Behavior, Bone marrow
Abstract

International audience; The production and regulation of red blood cells, erythropoiesis, occurs in the bone marrow where erythroid cells proliferate and differentiate within particular structures, called erythroblastic islands. A typical structure of these islands consists of a macrophage (white cell) surrounded by immature erythroid cells (progenitors), with more mature cells on the periphery of the island, ready to leave the bone marrow and enter the bloodstream. A hybrid model, coupling a continuous model (ordinary differential equations) describing intracellular regulation through competition of two key proteins, to a discrete spatial model describing cell-cell interactions, with growth factor diffusion in the medium described by a continuous model (partial differential equations), is proposed to investigate the role of the central macrophage in normal erythropoiesis. Intracellular competition of the two proteins leads the erythroid cell to either proliferation, differentiation, or death by apoptosis. This approach allows considering spatial aspects of erythropoiesis, involved for instance in the occurrence of cellular interactions or the access to external factors, as well as dynamics of intracellular and extracellular scales of this complex cellular process, accounting for stochasticity in cell cycle durations and orientation of the mitotic spindle. The analysis of the model shows a strong effect of the central macrophage on the stability of an erythroblastic island, when assuming the macrophage releases pro-survival cytokines. Even though it is not clear whether or not erythroblastic island stability must be required, investigation of the model concludes that stability improves responsiveness of the model, hence stressing out the potential relevance of the central macrophage in normal erythropoiesis.

Published
2011

16. An essential role for transcription before the MBT in Xenopus laevis

Author

Guillaume Luxardi, Jing Yang, Peter S. Klein, Laurent Kodjabachian, Jennifer Skirkanich, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), National Laboratory Infrared Phys. - shangai, and Chinese Academy of Sciences [Changchun Branch] (CAS)

Subjects
MESH: Signal Transduction, Embryo, Nonmammalian, animal structures, Transcription, Genetic, Nodal Protein, MESH: Feedback, Physiological, Xenopus, Nodal signaling, Smad Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Xenopus Proteins, Article, Midblastula, Xenopus laevis, 03 medical and health sciences, 0302 clinical medicine, MESH: Xenopus laevis, Transcription (biology), MESH: Gene Expression Regulation, Developmental, Animals, MESH: Animals, MESH: Blastula, MESH: Xenopus Proteins, MESH: Nodal Protein, Molecular Biology, Transcription factor, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Feedback, Physiological, Regulation of gene expression, 0303 health sciences, biology, MESH: Transcription, Genetic, Endoderm, Gene Expression Regulation, Developmental, MESH: Embryo, Nonmammalian, MESH: Smad Proteins, Cell Biology, Blastula, biology.organism_classification, Molecular biology, MESH: Endoderm, embryonic structures, Maternal to zygotic transition, NODAL, 030217 neurology & neurosurgery, Signal Transduction, Developmental Biology
Abstract

International audience; Most zygotic genes remain transcriptionally silent in Drosophila, Xenopus, and zebrafish embryos through multiple mitotic divisions until the midblastula transition (MBT). Several genes have been identified in each of these organisms that are transcribed before the MBT, but whether precocious expression of specific mRNAs is important for later development has not been examined in detail. Here, we identify a class of protein coding transcripts activated before the MBT by the maternal T-box factor VegT that are components of an established transcriptional regulatory network required for mesendoderm induction in Xenopus laevis, including the Nodal related ligands xnr5, xnr6, and derrière and the transcription factors bix4, and sox17α. Accumulation of phospho-Smad2, a hallmark of active Nodal signaling, at the onset of the MBT requires preMBT transcription and activity of xnr5 and xnr6. Furthermore, preMBT activation of the Nodal pathway is essential for mesendodermal gene expression and patterning of the embryo. Finally, xnr5 and xnr6 can also activate their own expression during cleavage stages, indicating that preMBT transcription contributes to a feed-forward system that allows robust activation of Nodal signaling at the MBT.

Published
2011

17. O-GlcNAc modification, insulin signaling and diabetic complications

Author

Tarik Issad, Elodie A.Y. Masson, P. Pagesy, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), ALFEDIAM 2007, ANR-Genopath 2008 'DIAB-O-GLYC', ARC-subvention 1069, région Ile-de-France, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UM3 (UMR 8104 / U1016)), and Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Signal Transduction, Glycosylation, MESH: Acetylglucosaminidase, MESH: Feedback, Physiological, MESH : Insulin, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Review, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, O-GlcNAcylation, MESH : Acetylglucosamine, Insulin, MESH: Animals, Receptor, Glucotoxicity, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 2. Zero hunger, Feedback, Physiological, 0303 health sciences, MESH: Acetylglucosamine, MESH : Glycosylation, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Glycosylation, MESH : Feedback, Physiological, MESH: Diabetes Complications, Insulin signaling, MESH : Diabetes Complications, MESH: N-Acetylglucosaminyltransferases, Phosphorylation, Signal transduction, Signal Transduction, medicine.medical_specialty, MESH: Receptor, Insulin, MESH: Insulin, Biology, N-Acetylglucosaminyltransferases, Acetylglucosamine, Diabetic complications, Diabetes Complications, 03 medical and health sciences, Insulin resistance, MESH : Acetylglucosaminidase, Diabetes mellitus, Internal medicine, Acetylglucosaminidase, Internal Medicine, medicine, Animals, Humans, MESH : Protein Processing, Post-Translational, 030304 developmental biology, MESH : Signal Transduction, MESH: Humans, MESH : N-Acetylglucosaminyltransferases, MESH : Humans, medicine.disease, Receptor, Insulin, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Insulin receptor, chemistry, Hyperglycemia, MESH: Protein Processing, Post-Translational, MESH : Receptor, Insulin, MESH : Hyperglycemia, biology.protein, MESH : Animals, MESH: Hyperglycemia, Protein Processing, Post-Translational, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery, Post-translational modifications
Abstract

International audience; O-GlcNAc glycosylation (O-GlcNAcylation) corresponds to the addition of N-acetylglucosamine on serine and threonine residues of cytosolic and nuclear proteins. O-GlcNAcylation is a dynamic post-translational modification, analogous to phosphorylation, that regulates the stability, the activity or the subcellular localisation of target proteins. This reversible modification depends on the availability of glucose and therefore constitutes a powerful mechanism by which cellular activities are regulated according to the nutritional environment of the cell. O-GlcNAcylation has been implicated in important human pathologies including Alzheimer disease and type-2 diabetes. Only two enzymes, OGT and O-GlcNAcase, control the O-GlcNAc level on proteins. Therefore, O-GlcNAcylations cannot organize in signaling cascades as observed for phosphorylations. O-GlcNAcylations should rather be considered as a "rheostat" that controls the intensity of the signals traveling through different pathways according to the nutritional status of the cell. Thus, OGT attenuates insulin signal by O-GlcNAcylation of proteins involved in proximal and distal steps in the PI-3 kinase signaling pathway. This negative feedback may be exacerbated when cells are chronically exposed to elevated glucose concentrations and could thereby contribute to alterations in insulin signaling observed in diabetic patients. O-GlcNAcylation also appears to contribute to the deleterious effects of hyperglycaemia on excessive glucose production by the liver and deterioration of β-cell pancreatic function, resulting in worsening of hyperglycaemia (glucotoxicity). Moreover, O-GlcNAcylations directly participate in several diabetic complications. O-GlcNAcylation of eNOS in endothelial cells have been involved in micro- and macrovascular complications. In addition, O-GlcNAcylations activate the expression of profibrotic and antifibrinolytic factors, contributing to vascular and renal dysfunctions.

Published
2010

18. TCR beta allelic exclusion in dynamical models of V(D)J recombination based on allele independence

Author

Sébastien Jaeger, Bastien Fernandez, Pierre Ferrier, Etienne Farcot, Salvatore Spicuglia, Marie Laure Bonnet, Modeling plant morphogenesis at different scales, from genes to phenotype (VIRTUAL PLANTS), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de la Recherche Agronomique (INRA)-Amélioration génétique et adaptation des plantes méditerranéennes et tropicales (UMR AGAP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Centre de Physique Théorique - UMR 6207 (CPT), Centre National de la Recherche Scientifique (CNRS)-Université de Toulon (UTLN)-Université de Provence - Aix-Marseille 1-Université de la Méditerranée - Aix-Marseille 2, Centre de Physique Théorique - UMR 7332 (CPT), Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro), Université de la Méditerranée - Aix-Marseille 2-Université de Provence - Aix-Marseille 1-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Dynamical modeling, MESH: Feedback, Physiological, Receptors, Antigen, T-Cell, alpha-beta, Immunoglobulin Variable Region, MESH: Immunoglobulin Variable Region, MESH: T-Lymphocyte Subsets, MESH: Mice, Knockout, Mice, 0302 clinical medicine, Models, T-Lymphocyte Subsets, Receptors, Immunology and Allergy, MESH: Animals, MESH: Molecular Dynamics Simulation, Genetics, Gene Rearrangement, alpha-beta, Feedback, Physiological, Mice, Knockout, Recombination, Genetic, 0303 health sciences, MESH: Receptors, Antigen, T-Cell, alpha-beta, V(D)J recombination, MESH: Gene Rearrangement, T-Lymphocyte, Markov Chains, Allelic exclusion, Immunological, Antigen, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunoglobulin Joining Region, MESH: Recombination, Genetic, Recombination, Antibody Diversity, Physiological, Knockout, Immunology, Locus (genetics), chemical and pharmacologic phenomena, MESH: Immunoglobulin Joining Region, Computational biology, Biology, Molecular Dynamics Simulation, Gene Rearrangement, T-Lymphocyte, MESH: Models, Immunological, Feedback, 03 medical and health sciences, Genetic, MESH: Markov Chains, Animals, Allele, MESH: Mice, Alleles, 030304 developmental biology, Markov chain, MESH: Alleles, T-cell receptor, Models, Immunological, MESH: Antibody Diversity, T-Cell, T-Lymphocyte, 030215 immunology
Abstract

Allelic exclusion represents a major aspect of TCRβ gene assembly by V(D)J recombination in developing T lymphocytes. Despite recent progress, its comprehension remains problematic when confronted with experimental data. Existing models fall short in terms of incorporating into a unique distribution all the cell subsets emerging from the TCRβ assembly process. To revise this issue, we propose dynamical, continuous-time Markov chain-based modeling whereby essential steps in the biological procedure (D-J and V-DJ rearrangements and feedback inhibition) evolve independently on the two TCRβ alleles in every single cell while displaying random modes of initiation and duration. By selecting parameters via fitting procedures, we demonstrate the capacity of the model to offer accurate fractions of all distinct TCRβ genotypes observed in studies using developing and mature T cells from wild-type or mutant mice. Selected parameters in turn afford relative duration for each given step, hence updating TCRβ recombination distinctive timings. Overall, our dynamical modeling integrating allele independence and noise in recombination and feedback-inhibition events illustrates how the combination of these ingredients alone may enforce allelic exclusion at the TCRβ locus.

Published
2010

19. Endogenous morphine signaling via nitric oxide regulates the expression of CYP2D6 and COMT: autocrine/paracrine feedback inhibition

Author

Patrick Cadet, George B. Stefano, Gregory L. Fricchione, Yannick Goumon, Tobias Esch, Kirk J. Mantione, Wei Zhu, Melinda Sheehan, Richard M. Kream, College at Old Westbury [SUNY] (SUNY Old Westbury), State University of New York (SUNY), Massachusetts General Hospital [Boston], Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie du système nerveux., Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), Coburg University of Applied Sciences and Arts, and Goumon, Yannick

Subjects
MESH: Signal Transduction, MESH: Feedback, Physiological, Narcotic Antagonists, Receptors, Opioid, mu, Medicine (miscellaneous), (+)-Naloxone, Pharmacology, MESH: Naloxone, MESH: Down-Regulation, chemistry.chemical_compound, [SCCO]Cognitive science, MESH: NG-Nitroarginine Methyl Ester, MESH: Reverse Transcriptase Polymerase Chain Reaction, Leukocytes, Receptor, Oligonucleotide Array Sequence Analysis, Feedback, Physiological, Morphine, Naloxone, Reverse Transcriptase Polymerase Chain Reaction, MESH: Gene Expression Regulation, Enzymologic, MESH: S-Nitroso-N-Acetylpenicillamine, Autocrine Communication, Psychiatry and Mental health, NG-Nitroarginine Methyl Ester, Cytochrome P-450 CYP2D6, MESH: Narcotic Antagonists, Opiate, Signal Transduction, medicine.drug, medicine.medical_specialty, MESH: Catechol O-Methyltransferase, Down-Regulation, MESH: Receptors, Opioid, mu, S-Nitroso-N-Acetylpenicillamine, Catechol O-Methyltransferase, Nitric Oxide, Gene Expression Regulation, Enzymologic, MESH: Cytochrome P-450 CYP2D6, Nitric oxide, MESH: Leukocytes, Paracrine signalling, Internal medicine, Paracrine Communication, medicine, Humans, RNA, Messenger, MESH: Paracrine Communication, Autocrine signalling, MESH: RNA, Messenger, MESH: Humans, [SCCO] Cognitive science, Endocrinology, MESH: Morphine, chemistry, Opioid, MESH: Nitric Oxide, MESH: Oligonucleotide Array Sequence Analysis, MESH: Autocrine Communication
Abstract

International audience; We determined changes in mRNA expression in specific enzymes involved in the biosynthesis of morphine in human white blood cells via microarray. Leukocyte exposure to morphine down-regulated catechol-O-methyl transferase (COMT) and CYP2D6 by approximately 50% compared with control values. The treatment did not alter DOPA decarboxylase and dopamine beta-hydroxylase expression, demonstrating the specificity of morphine actions. The verification of the microarray data was accomplished via real-time Taqman reverse transcriptase polymerase chain reaction (RT-PCR) focused on CYP2D6 and COMT expression in different blood samples treated with morphine. The analysis showed similar changes in the expression of CYP2D6 and COMT mRNA. The expression was reduced by 47 +/- 7% for CYP2D6, substantiating the microarray finding of a 54% reduction. Furthermore, exposure of white blood cells to 10(-6) M S-nitroso-N-acetyl-DL-penicillamine (SNAP), a nitric oxide (NO) donor, reduced the expression of CYP2D6 and COMT. Prior naloxone (10(-6) M) or N-nitro-L-arginine methyl ester (L-NAME) (10(-4) M) addition abrogated morphine's down-regulating activity, demonstrating morphine was initiating its actions via stimulating constitutive NO synthase derived NO release via the mu3 opiate receptor splice variant. In the past we demonstrated that UDP-glucurosyltransferase is involved in metabolizing morphine to morphine 6-glucuronide in adrenal chromaffin cells. In the present study its expression was not found in controls and morphine-treated cells, suggesting that morphine 6-glucuronide may not be synthesized in white blood cells. Taken together, it appears that morphine has the ability to modulate its own synthesis via autocrine and paracrine signaling.

Published
2008

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