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1. A fatty acid anabolic pathway in specialized-cells sustains a remote signal that controls egg activation in Drosophila.

Author

Mickael Poidevin, Nicolas Mazuras, Gwénaëlle Bontonou, Pierre Delamotte, Béatrice Denis, Maëlle Devilliers, Perla Akiki, Delphine Petit, Laura de Luca, Priscilla Soulie, Cynthia Gillet, Claude Wicker-Thomas, and Jacques Montagne

Subjects
Genetics, QH426-470
Abstract

Egg activation, representing the critical oocyte-to-embryo transition, provokes meiosis completion, modification of the vitelline membrane to prevent polyspermy, and translation of maternally provided mRNAs. This transition is triggered by a calcium signal induced by spermatozoon fertilization in most animal species, but not in insects. In Drosophila melanogaster, mature oocytes remain arrested at metaphase-I of meiosis and the calcium-dependent activation occurs while the oocyte moves through the genital tract. Here, we discovered that the oenocytes of fruitfly females are required for egg activation. Oenocytes, cells specialized in lipid-metabolism, are located beneath the abdominal cuticle. In adult flies, they synthesize the fatty acids (FAs) that are the precursors of cuticular hydrocarbons (CHCs), including pheromones. The oenocyte-targeted knockdown of a set of FA-anabolic enzymes, involved in very-long-chain fatty acid (VLCFA) synthesis, leads to a defect in egg activation. Given that some but not all of the identified enzymes are required for CHC/pheromone biogenesis, this putative VLCFA-dependent remote control may rely on an as-yet unidentified CHC or may function in parallel to CHC biogenesis. Additionally, we discovered that the most posterior ventral oenocyte cluster is in close proximity to the uterus. Since oocytes dissected from females deficient in this FA-anabolic pathway can be activated in vitro, this regulatory loop likely operates upstream of the calcium trigger. To our knowledge, our findings provide the first evidence that a physiological extra-genital signal remotely controls egg activation. Moreover, our study highlights a potential metabolic link between pheromone-mediated partner recognition and egg activation.

Published
2024
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2. A simple and efficient process for the synthesis of 2D carbon nitrides and related materials

Author

Cora Moreira Da Silva, Maxime Vallet, Clément Semion, Thomas Blin, Romuald Saint-Martin, Jocelyne Leroy, Diana Dragoé, François Brisset, Cynthia Gillet, Régis Guillot, and Vincent Huc

Subjects
Medicine, Science
Abstract

Abstract We describe here a new process for the synthesis of very high quality 2D Covalent Organic Frameworks (COFs), such a C2N and CN carbon nitrides. This process relies on the use of a metallic surface as both a reagent and a support for the coupling of small halogenated building blocks. The conditions of the assembly reaction are chosen so as to leave the inorganic salts by-products on the surface, to further confine the assembly reaction on the surface and increase the quality of the 2D layers. We found that under these conditions, the process directly returns few layers material. The structure/quality of these materials is demonstrated by extensive cross-characterizations at different scales, combining optical microscopy, Scanning Electron Microscopy (SEM)/Transmission Electron Microscopy (TEM) and Energy Dispersive Spectroscopy (EDS). The availability of such very large, high-quality layers of these materials opens interesting perspectives, for example in photochemistry and electronics (intrinsic transport properties, high gap substrate for graphene, etc...).

Published
2023
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3. Amorphous Calcium Carbonate Granules Form Within an Intracellular Compartment in Calcifying Cyanobacteria

Author

Marine Blondeau, Martin Sachse, Claire Boulogne, Cynthia Gillet, Jean-Michel Guigner, Fériel Skouri-Panet, Mélanie Poinsot, Céline Ferard, Jennyfer Miot, and Karim Benzerara

Subjects
amorphous calcium carbonate, cyanobacteria, biomineralization, freeze-substitution, CEMOVIS, bacterial microcompartment, Microbiology, QR1-502
Abstract

The recent discovery of cyanobacteria forming intracellular amorphous calcium carbonate (ACC) has challenged the former paradigm suggesting that cyanobacteria-mediated carbonatogenesis was exclusively extracellular. Yet, the mechanisms of intracellular biomineralization in cyanobacteria and in particular whether this takes place within an intracellular microcompartment, remain poorly understood. Here, we analyzed six cyanobacterial strains forming intracellular ACC by transmission electron microscopy. We tested two different approaches to preserve as well as possible the intracellular ACC inclusions: (i) freeze-substitution followed by epoxy embedding and room-temperature ultramicrotomy and (ii) high-pressure freezing followed by cryo-ultramicrotomy, usually referred to as cryo-electron microscopy of vitreous sections (CEMOVIS). We observed that the first method preserved ACC well in 500-nm-thick sections but not in 70-nm-thick sections. However, cell ultrastructures were difficult to clearly observe in the 500-nm-thick sections. In contrast, CEMOVIS provided a high preservation quality of bacterial ultrastructures, including the intracellular ACC inclusions in 50-nm-thick sections. ACC inclusions displayed different textures, suggesting varying brittleness, possibly resulting from different hydration levels. Moreover, an electron dense envelope of ∼2.5 nm was systematically observed around ACC granules in all studied cyanobacterial strains. This envelope may be composed of a protein shell or a lipid monolayer, but not a lipid bilayer as usually observed in other bacteria forming intracellular minerals. Overall, this study evidenced that ACC inclusions formed and were stabilized within a previously unidentified bacterial microcompartment in some species of cyanobacteria.

Published
2018
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4. Dp71 contribution to the molecular scaffold anchoring aquaporine‐4 channels in brain macroglial cells

Author

Cyrille Vaillend, Jean-Vianney Barnier, Alvaro Rendon, Charlotte Izabelle, Mehdi Belmaati Cherkaoui, Claire Boulogne, Ophélie Vacca, Martine Cohen-Salmon, Cynthia Gillet, Anne-Cécile Boulay, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Microscopie Électronique (MET), Département Plateforme (PF I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-14-CE13-0037,DYSther,Dystrophines Dans Le Système Nerveux : De la Neurophysiologie à la Thérapie Moléculaire(2014), ANR-11-EQPX-0029,MORPHOSCOPE 2,Imagerie et reconstruction multiéchelles de la morphogenèse. (Plateforme d'innovation technologique et méthodologique pour l'imagerie in vivo et la reconstruction des dynamiques multiéchelles de la morphogenèse)(2011), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-LABX-0040,SPS,Saclay Plant Sciences(2010), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Cerebellum, glymphatic system, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Hippocampus, Blood–brain barrier, Dystrophin, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Cortex (anatomy), medicine, Animals, Dystroglycans, Aquaporin 4, biology, Brain, Immunogold labelling, blood-brain barrier, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Neurology, Hippocampal Fissure, Astrocytes, intellectual disability, biology.protein, Glymphatic system, gliovascular unit, Neuroglia, 030217 neurology & neurosurgery
Abstract

International audience; Intellectual disability in Duchenne muscular dystrophy has been associated with the loss of dystrophin-protein 71, Dp71, the main dystrophin-gene product in the adult brain. Dp71 shows major expression in perivascular macroglial endfeet, suggesting that dysfunctional glial mechanisms contribute to cognitive impairments. In the present study, we investigated the molecular alterations induced by a selective loss of Dp71 in mice, using semi-quantitative immunogold analyses in electron microscopy and immunofluorescence confocal analyses in brain sections and purified gliovascular units. In macroglial pericapillary endfeet of the cerebellum and hippocampus, we found a drastic reduction (70%) of the polarized distribution of aquaporin-4 (AQP4) channels, a 50% reduction of β-dystroglycan, and a complete loss of α1-syntrophin. Interestingly, in the hippocampus and cortex, these effects were not homogeneous: AQP4 and AQP4ex isoforms were mostly lost around capillaries but preserved in large vessels corresponding to pial arteries, penetrating cortical arterioles, and arterioles of the hippocampal fissure, indicating the presence of Dp71-independent pools of AQP4 in these vascular structures. In conclusion, the depletion of Dp71 strongly alters the distribution of AQP4 selectively in macroglial perivascular endfeet surrounding capillaries. This effect likely affects water homeostasis and blood-brain barrier functions and may thus contribute to the synaptic and cognitive defects associated with Dp71 deficiency.

Published
2020

5. Caveolin-1β promotes the production of active human microsomal glutathione S-transferase in induced intracellular vesicles inSpodoptera frugiperda21 insect cells

Author

Nahuel, Perrot, Delphine, Dessaux, Anthony, Rignani, Cynthia, Gillet, Stéphane, Orlowski, Nadège, Jamin, Manuel, Garrigos, and Christine, Jaxel

Subjects
Dogs, Insecta, Caveolin 1, Animals, Humans, Membrane Proteins, Glutathione, Glutathione Transferase
Abstract

The heterologous expression in Spodoptera frugiperda 21 (Sf21) insect cells of the β isoform of canine caveolin-1 (caveolin-1β), using a baculovirus-based vector, resulted in intracellular vesicles enriched in caveolin-1β. We investigated whether these vesicles could act as membrane reservoirs, and promote the production of an active membrane protein (MP) when co-expressed with caveolin-1β. We chose hMGST1 (human microsomal glutathione S-transferase 1) as the co-expressed MP. It belongs to the membrane-associated proteins in eicosanoid and glutathione metabolism (MAPEG) family of integral MPs, and, as a phase II detoxification enzyme, it catalyzes glutathione conjugation of lipophilic drugs present in the lipid membranes. In addition to its pharmaceutical interest, its GST activity can be conveniently measured. The expression of both MPs were followed by Western blots and membrane fractionation on density gradient, and their cell localization by immunolabeling and transmission electron microscopy. We showed that caveolin-1β kept its capacity to induce intracellular vesicles in the host when co-expressed with hMGST1, and that hMGST1 is in part addressed to these vesicles. Remarkably, a fourfold increase in the amount of active hMGST1 was found in the most enriched membrane fraction, along with an increase of its specific activity by 60% when it was co-expressed with caveolin-1β. Thus, heterologously expressed caveolin-1β was able to induce cytoplasmic vesicles in which a co-expressed exogenous MP is diverted and sequestered, providing a favorable environment for this cargo.

Published
2021

6. NEM6, KBTBD13-Related Congenital Myopathy: Myopathological Analysis in 18 Dutch Patients Reveals Ring Rods Fibers, Cores, Nuclear Clumps, and Granulo-Filamentous Protein Material

Author

Nicol C. Voermans, Claire Boulogne, Benno Küsters, Clémence Labasse, Baziel G.M. van Engelen, Coen A.C. Ottenheijm, Josine M. de Winter, Guy Brochier, Karlijn Bouman, Lilian Eshuis, Esmee S.B. Van Kleef, Norma B. Romero, A. Madelaine, Cynthia Gillet, Edoardo Malfatti, Physiology, and ACS - Pulmonary hypertension & thrombosis

Subjects
Adult, Male, Pathology, medicine.medical_specialty, genetic structures, Muscle Fibers, Skeletal, Muscle Proteins, Myopathies, Nemaline, Sarcomere, Pathology and Forensic Medicine, law.invention, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Nemaline myopathy, law, medicine, Myotilin, Humans, Myopathy, Actin, 030304 developmental biology, Aged, Netherlands, 0303 health sciences, biology, Chemistry, General Medicine, Middle Aged, medicine.disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Congenital myopathy, Neurology, biology.protein, Titin, Female, Neurology (clinical), sense organs, medicine.symptom, Electron microscope, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 232919.pdf (Publisher’s version ) (Closed access) Nemaline myopathy type 6 (NEM6), KBTBD13-related congenital myopathy is caused by mutated KBTBD13 protein that interacts improperly with thin filaments/actin, provoking impaired muscle-relaxation kinetics. We describe muscle morphology in 18 Dutch NEM6 patients and correlate it with clinical phenotype and pathophysiological mechanisms. Rods were found in in 85% of biopsies by light microscopy, and 89% by electron microscopy. A peculiar ring disposition of rods resulting in ring-rods fiber was observed. Cores were found in 79% of NEM6 biopsies by light microscopy, and 83% by electron microscopy. Electron microscopy also disclosed granulofilamentous protein material in 9 biopsies. Fiber type 1 predominance and prominent nuclear internalization were found. Rods were immunoreactive for α-actinin and myotilin. Areas surrounding the rods showed titin overexpression suggesting derangement of the surrounding sarcomeres. NEM6 myopathology hallmarks are prominent cores, rods including ring-rods fibers, nuclear clumps, and granulofilamentous protein material. This material might represent the histopathologic epiphenomenon of altered interaction between mutated KBTBD13 protein and thin filaments. We claim to classify KBTBD13-related congenital myopathy as rod-core myopathy.

Published
2021

7. ABMA, a small molecule that inhibits intracellular toxins and pathogens by interfering with late endosomal compartments

Author

Didier Sauvaire, Philippe M. Loiseau, Sabrina Kali, Rahima Yousfi, Pascal Clayette, Daniel Gillet, Céline Bouclier, Noël Tordo, Jérôme Laporte, Amélie Goudet, Goulven Merer, Roman Lopez, Michel R. Popoff, Sandrine Cojean, Valérie Pons, Céline Aubenque, Claire Boulogne, Emmanuel Lemichez, Annette Fischer, Jean-Christophe Cintrat, Laetitia Panigai, Yu Wu, Cynthia Gillet, Roger Le Grand, Thomas Rudel, Robert A. Davey, Julien Barbier, Jo-Ana Herweg, Emilie Gobbo, Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Chimie Bio-Organique et de Marquage (SCBM), Agence nationale de sécurité du médicament et des produits de santé [Saint-Denis] (ANSM), Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Stratégies antivirales, Institut Pasteur [Paris], Texas Biomedical Research Institute, CEA [Fontenay-aux-Roses] (UGRA / SETA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Molécules bioactives, conception, isolement et synthèse (MBCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Bactéries anaérobies et Toxines, Pharmacologie des rétrovirus, Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work has been funded by the joint ministerial program of R&D against CBRNE risks and CEA, and benefited from the core facilities of Imagerie-Gif (http://www.i2bc.paris-saclay.fr), member of IBiSA (http://www.ibisa.net), supported by 'France-BioImaging' (ANR-10-INBS-04–01) and the Labex 'Saclay Plant Science' (ANR-11-IDEX-0003–02). This work was also supported by U.S. National Institutes of Health and National Institute of Allergy and Infectious Diseases grant R01AI063513, Defense Threat Reduction Agency grant HDTRA1–12–1–0002, and the Douglass and Ewing Halsell Foundations. Work on Simkania and Chlamydia was supported by the Deutsche Forschungsgemeinschaft (DFG) Priority programme 1580 to T.R. SIMOPRO and SCBM are members of the Laboratory of Excellence LERMIT supported by a grant from the Agence Nationale de la Recherche (ANR-10-LABX-33) and RetroLeishma project R3, We greatfully thank Anne Doye (Université de Nice Sophia-Antipolis) for technical assistance and Bruno Beaumelle for providing ricin, ANR-11-IDEX-0002,UNITI,Université Fédérale de Toulouse(2011), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-11-IDEX-0003,IPS,Idex Paris-Saclay(2011), Julius-Maximilians-Universität Würzburg (JMU), Institut Pasteur [Paris] (IP), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Popoff, Michel, Initiative d'excellence - Université Fédérale de Toulouse - - UNITI2011 - ANR-11-IDEX-0002 - IDEX - VALID, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, and Idex Paris-Saclay - - IPS2011 - ANR-11-IDEX-0003 - IDEX - VALID

Subjects
0301 basic medicine, Benzylamines, Endosome, 030106 microbiology, Cell, Golgi Apparatus, lcsh:Medicine, Adamantane, Endosomes, Ricin, Endoplasmic Reticulum, Article, Mice, 03 medical and health sciences, symbols.namesake, ddc:570, Benzyl Compounds, Organelle, medicine, Animals, Humans, lcsh:Science, Pathogen, Toxins, Biological, Multidisciplinary, Chemistry, Antimicrobials, Endoplasmic reticulum, Intracellular parasite, lcsh:R, High-throughput screening, Golgi apparatus, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Cell Compartmentation, 3. Good health, Cell biology, 030104 developmental biology, medicine.anatomical_structure, symbols, Infectious diseases, lcsh:Q, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Lysosomes, Intracellular, HeLa Cells
Abstract

Intracellular pathogenic microorganisms and toxins exploit host cell mechanisms to enter, exert their deleterious effects as well as hijack host nutrition for their development. A potential approach to treat multiple pathogen infections and that should not induce drug resistance is the use of small molecules that target host components. We identified the compound 1-adamantyl (5-bromo-2-methoxybenzyl) amine (ABMA) from a cell-based high throughput screening for its capacity to protect human cells and mice against ricin toxin without toxicity. This compound efficiently protects cells against various toxins and pathogens including viruses, intracellular bacteria and parasite. ABMA provokes Rab7-positive late endosomal compartment accumulation in mammalian cells without affecting other organelles (early endosomes, lysosomes, the Golgi apparatus, the endoplasmic reticulum or the nucleus). As the mechanism of action of ABMA is restricted to host-endosomal compartments, it reduces cell infection by pathogens that depend on this pathway to invade cells. ABMA may represent a novel class of broad-spectrum compounds with therapeutic potential against diverse severe infectious diseases.

Published
2017

9. S6 kinase 1 is required for rapamycin-sensitive liver proliferation after mouse hepatectomy

Author

Cynthia Gillet, Jeffrey H. Albrecht, Céline Chauvin, Séverine Celton-Morizur, Vonda Koka, Claudia Mitchell, Mario Pende, Catherine Espeillac, and Chantal Desdouets

Subjects
Genotype, Cyclin A, P70-S6 Kinase 1, mTORC1, Mechanistic Target of Rapamycin Complex 1, Ribosomal Protein S6 Kinases, 90-kDa, Mice, Animals, Hepatectomy, Cyclin D1, Cells, Cultured, PI3K/AKT/mTOR pathway, Cell Proliferation, Mice, Knockout, Sirolimus, Antibiotics, Antineoplastic, biology, Cell growth, TOR Serine-Threonine Kinases, Cell Cycle, Cyclin-dependent kinase 3, Proteins, General Medicine, Cell cycle, Liver Regeneration, Cell biology, Isoenzymes, Mice, Inbred C57BL, Liver, Multiprotein Complexes, Hepatocytes, biology.protein, Research Article
Abstract

Rapamycin is an antibiotic inhibiting eukaryotic cell growth and proliferation by acting on target of rapamycin (TOR) kinase. Mammalian TOR (mTOR) is thought to work through 2 independent complexes to regulate cell size and cell replication, and these 2 complexes show differential sensitivity to rapamycin. Here we combine functional genetics and pharmacological treatments to analyze rapamycin-sensitive mTOR substrates that are involved in cell proliferation and tissue regeneration after partial hepatectomy in mice. After hepatectomy, hepatocytes proliferated rapidly, correlating with increased S6 kinase phosphorylation, while treatment with rapamycin derivatives impaired regeneration and blocked S6 kinase activation. In addition, genetic deletion of S6 kinase 1 (S6K1) caused a delay in S phase entry in hepatocytes after hepatectomy. The proliferative defect of S6K1-deficient hepatocytes was cell autonomous, as it was also observed in primary cultures and hepatic overexpression of S6K1-rescued proliferation. We found that S6K1 controlled steady-state levels of cyclin D1 (Ccnd1) mRNA in liver, and cyclin D1 expression was required to promote hepatocyte cell cycle. Notably, in vivo overexpression of cyclin D1 was sufficient to restore the proliferative capacity of S6K-null livers. The identification of an S6K1-dependent mechanism participating in cell proliferation in vivo may be relevant for cancer cells displaying high mTOR complex 1 activity and cyclin D1 accumulation.

Published
2011

10. Bypassing Iron Storage in Endodermal Vacuoles Rescues the Iron Mobilization Defect in the \textitnatural resistance associated-macrophage protein3natural resistance associated-macrophage protein4 Double Mutant

Author

Magali Schnell Ramos, Colin Clairet, Amanda Socha, Jérôme Giraudat, Cynthia Gillet, Astrid Agorio, Sébastien Thomine, Sun A. Kim, Mary Lou Guerinot, Tracy Punshon, Sylvain Merlot, Viviane Mary, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Approches intégratives du Transport Ionique (MINION), Département Biologie Cellulaire (BioCell), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
0106 biological sciences, X-Ray Emission, Physiology, [SDV]Life Sciences [q-bio], Messenger, Arabidopsis, Plant Science, Vacuole, 01 natural sciences, Plant Epidermis, Gene Knockout Techniques, Models, Arabidopsis thaliana, Suppressor, Cation Transport Proteins, ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, education.field_of_study, Embryo, Phenotype, Cell biology, Cotyledon, Subcellular Fractions, Iron, Population, Germination, Biology, 03 medical and health sciences, education, Alleles, 030304 developmental biology, Arabidopsis Proteins, Spectrometry, Transporter, Biological Transport, Plant, Vascular bundle, biology.organism_classification, Biological, Gene Expression Regulation, Genes, Mutagenesis, Seedlings, Mutation, Vacuoles, RNA, 010606 plant biology & botany
Abstract

To improve seed iron (Fe) content and bioavailability, it is crucial to decipher the mechanisms that control Fe storage during seed development. In Arabidopsis (Arabidopsis thaliana) seeds, most Fe is concentrated in insoluble precipitates, with phytate in the vacuoles of cells surrounding the vasculature of the embryo. NATURAL RESISTANCE ASSOCIATED-MACROPHAGE PROTEIN3 (AtNRAMP3) and AtNRAMP4 function redundantly in Fe retrieval from vacuoles during germination. When germinated under Fe-deficient conditions, development of the nramp3nramp4 double mutant is arrested as a consequence of impaired Fe mobilization. To identify novel genes involved in seed Fe homeostasis, we screened an ethyl methanesulfonate-mutagenized population of nramp3nramp4 seedlings for mutations suppressing their phenotypes on low Fe. Here, we report that, among the suppressors, two independent mutations in the VACUOLAR IRON TRANSPORTER1 (AtVIT1) gene caused the suppressor phenotype. The AtVIT1 transporter is involved in Fe influx into vacuoles of endodermal and bundle sheath cells. This result establishes a functional link between Fe loading in vacuoles by AtVIT1 and its remobilization by AtNRAMP3 and AtNRAMP4. Moreover, analysis of subcellular Fe localization indicates that simultaneous disruption of AtVIT1, AtNRAMP3, and AtNRAMP4 limits Fe accumulation in vacuolar globoids.

Published
2015

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