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1. Single cell RNA sequencing reveals hemocyte heterogeneity in Biomphalaria glabrata: Plasticity over diversity

Author

Rémi Pichon, Silvain Pinaud, Emmanuel Vignal, Cristian Chaparro, Marine Pratlong, Anaïs Portet, David Duval, Richard Galinier, and Benjamin Gourbal

Subjects
single cell RNA seq, B. glabrata, hemocytes, innate immune system, S. mansoni, Immunologic diseases. Allergy, RC581-607
Abstract

The freshwater snail Biomphalaria glabrata is an intermediate host of Schistosoma mansoni, the agent of human intestinal schistosomiasis. However, much is to be discovered about its innate immune system that appears as a complex black box, in which the immune cells (called hemocytes) play a major role in both cellular and humoral response towards pathogens. Until now, hemocyte classification has been based exclusively on cell morphology and ultrastructural description and depending on the authors considered from 2 to 5 hemocyte populations have been described. In this study, we proposed to evaluate the hemocyte heterogeneity at the transcriptomic level. To accomplish this objective, we used single cell RNA sequencing (scRNAseq) technology coupled to a droplet-based system to separate hemocytes and analyze their transcriptome at a unique cell level in naive Biomphalaria glabrata snails. We were able to demonstrate the presence of 7 hemocyte transcriptomic populations defined by the expression of specific marker genes. As a result, scRNAseq approach showed a high heterogeneity within hemocytes, but provides a detailed description of the different hemocyte transcriptomic populations in B. glabrata supported by distinct cellular functions and lineage trajectory. As a main result, scRNAseq revealed the 3 main population as a super-group of hemocyte diversity but, on the contrary, a great hemocytes plasticity with a probable capacity of hemocytes to engage to different activation pathways. This work opens a new field of research to understand the role of hemocytes particularly in response to pathogens, and towards S. mansoni parasites.

Published
2022
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3. Evolution of the Rho Family of Ras-Like GTPases in Eukaryotes

Author

Emmanuel Vignal, Philippe Fort, Sandrine Faure, Anthony Boureux, Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherches de biochimie macromoléculaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-IFR122-Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherches sur les Herbivores - UMR 1213 (UMRH), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-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)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Philippe, Fort

Subjects
rho GTP-Binding Proteins, Subfamily, MESH: Plants, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], MESH: Amino Acid Sequence, CDC42, GTPase, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, 0302 clinical medicine, Gene Duplication, MESH: Pseudogenes, MESH: Animals, MESH: Phylogeny, MESH: Vertebrates, Phylogeny, ComputingMilieux_MISCELLANEOUS, MESH: Evolution, Molecular, 0303 health sciences, MESH: Gene Duplication, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, cytoskeleton, Plants, Cell biology, 030220 oncology & carcinogenesis, Vertebrates, Pseudogenes, MESH: Fungi, Pseudogene, Molecular Sequence Data, MESH: Sequence Alignment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Chordate, RAC1, Biology, Article, Evolution, Molecular, 03 medical and health sciences, MESH: Invertebrates, [SDV.CAN] Life Sciences [q-bio]/Cancer, Rho, [SDV.BID.SPT] Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, evolution, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Genetics, Animals, Humans, cell signaling, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, RhoBTB, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, MESH: Molecular Sequence Data, MESH: Humans, Alternative splicing, Fungi, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: rho GTP-Binding Proteins, biology.organism_classification, Invertebrates, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Sequence Alignment
Abstract

International audience; GTPases of the Rho family are molecular switches that play important roles in converting and amplifying external signals into cellular effects. Originally de onstrated to control the dynamics of the F-actin cytoskeleton, Rho GTPases have been implicated in many basic cellular processes that influence cell proliferation, differentiation, motility, adhesion, survival, or secretion. To elucidate the evolutionary history of the Rho family, we have analyzed over 20 species covering major eukaryotic clades from unicellular organisms to mammals, including platypus and opossum, and have reconstructed the ontogeny and the chronology of emergence of the different subfamilies. Our data establish that the 20 mammalian Rho members are structured into 8 subfamilies, among which Rac is the founder of the whole family. Rho, Cdc42, RhoUV, and RhoBTB subfamilies appeared before Coelomates and RhoJQ, Cdc42 isoforms, RhoDF, and Rnd emerged in chordates. In vertebrates, gene duplications and retrotranspositions increased the size of each chordate Rho subfamily, whereas RhoH, the last subfamily, arose probably by horizontal gene transfer. Rac1b, a Rac1 isoform generated by alternative splicing, emerged in amniotes, and RhoD, only in therians. Analysis of Rho mRNA expression patterns in mouse tissues shows that recent subfamilies have tissue-specific and low-level expression that supports their implication only in narrow time windows or in differentiated metabolic functions. These findings give a comprehensive view of the evolutionary canvas of the Rho family and provide guides for future structure and evolution studies of other components of Rho signaling pathways, in particular regulators of the RhoGEF family.

Published
2006
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4. Cdc42Hs and Rac1 GTPases Induce the Collapse of the Vimentin Intermediate Filament Network

Author

Franck Comunale, Sophie Mary, Philippe Fort, Cécile Gauthier-Rouvière, Emmanuel Vignal, Mayya Meriane, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Centre de recherches de biochimie macromoléculaire (CRBM), and Centre National de la Recherche Scientifique (CNRS)-IFR122-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1)

Subjects
rac1 GTP-Binding Protein, Intermediate Filaments, [SDV.CAN]Life Sciences [q-bio]/Cancer, RAC1, Vimentin, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], macromolecular substances, GTPase, Transfection, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Biochemistry, Cell Line, Wortmannin, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Animals, Humans, Phosphorylation, Phosphotyrosine, cdc42 GTP-Binding Protein, Intermediate filament, Molecular Biology, 030304 developmental biology, 0303 health sciences, biology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Tyrosine phosphorylation, Cell Biology, Fibroblasts, Embryo, Mammalian, Molecular biology, Actins, Recombinant Proteins, Rats, Cell biology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, chemistry, 030220 oncology & carcinogenesis, biology.protein, RhoG
Abstract

International audience; In this study we show that expression of active Cdc42Hs and Rac1 GTPases, two Rho family members, leads to the reorganization of the vimentin intermediate filament (IF) network, showing a perinuclear collapse. Cdc42Hs displays a stronger effect than Rac1 as 90% versus 75% of GTPase-expressing cells show vimentin collapse. Similar vimentin IF modifications were observed when endogenous Cdc42Hs was activated by bradykinin treatment, endogenous Rac1 by platelet-derived growth factor/epidermal growth factor, or both endogenous proteins upon expression of active RhoG. This reorganization of the vimentin IF network is not associated with any significant increase in soluble vimentin. Using effector loop mutants of Cdc42Hs and Rac1, we show that the vimentin collapse is mostly independent of CRIB (Cdc42Hs or Rac-interacting binding)-mediated pathways such as JNK or PAK activation but is associated with actin reorganization. This does not result from F-actin depolymerization, because cytochalasin D treatment or Scar-WA expression have merely no effect on vimentin organization. Finally, we show that genistein treatment of Cdc42 and Rac1-expressing cells strongly reduces vimentin collapse, whereas staurosporin, wortmannin, LY-294002, R(p)-cAMP, or RII, the regulatory subunit of protein kinase A, remain ineffective. Moreover, we detected an increase in cellular tyrosine phosphorylation content after Cdc42Hs and Rac1 expression without modification of the vimentin phosphorylation status. These data indicate that Cdc42Hs and Rac1 GTPases control vimentin IF organization involving tyrosine phosphorylation events.

Published
2000
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5. TrioGEF1 controls Rac- and Cdc42-dependent cell structures through the direct activation of rhoG

Author

Cécile Gauthier-Rouvière, Anne Debant, Anne Blangy, Emmanuel Vignal, Philippe Fort, Susanne Schmidt, Centre de recherches de biochimie macromoléculaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-IFR122-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-IFR122-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1)

Subjects
rac1 GTP-Binding Protein, MESH: Signal Transduction, GTP', MESH: Guanosine Diphosphate, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], GTPase, CDC42, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Microtubules, GTP Phosphohydrolases, MESH: Protein Structure, Tertiary, 0302 clinical medicine, Genes, Reporter, Yeasts, MESH: Animals, cdc42 GTP-Binding Protein, MESH: Peptide Fragments, Cells, Cultured, Genes, Dominant, MESH: Mutagenesis, 0303 health sciences, MESH: Guanosine Triphosphate, MESH: Microtubules, MESH: Yeasts, MESH: Indicators and Reagents, MESH: Transcription Factors, Cell biology, MESH: Luminescent Proteins, Guanosine Triphosphate, Signal Transduction, MESH: Cells, Cultured, Binding domain, MESH: GTP Phosphohydrolases, MESH: Microscopy, Electron, Scanning, MESH: Rats, Recombinant Fusion Proteins, Green Fluorescent Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, RAC1, Protein Serine-Threonine Kinases, Biology, MESH: Actins, MESH: Two-Hybrid System Techniques, Guanosine Diphosphate, MESH: Phosphoproteins, MESH: Protein-Serine-Threonine Kinases, 03 medical and health sciences, MESH: Green Fluorescent Proteins, Microtubule, Two-Hybrid System Techniques, MESH: Recombinant Fusion Proteins, Extracellular, Animals, 030304 developmental biology, MESH: cdc42 GTP-Binding Protein, MESH: rac1 GTP-Binding Protein, MESH: Genes, Reporter, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Fibroblasts, Phosphoproteins, Actins, Peptide Fragments, Protein Structure, Tertiary, Rats, Luminescent Proteins, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Mutagenesis, MESH: Fibroblasts, Microscopy, Electron, Scanning, Indicators and Reagents, RhoG, MESH: Genes, Dominant, 030217 neurology & neurosurgery, Transcription Factors
Abstract

International audience; Rho GTPases regulate the morphology of cells stimulated by extracellular ligands. Their activation is controlled by guanine exchange factors (GEF) that catalyze their binding to GTP. The multidomain Trio protein represents an emerging class of &Rgr; regulators that contain two GEF domains of distinct specificities. We report here the characterization of Rho signaling pathways activated by the N-terminal GEF domain of Trio (TrioD1). In fibroblasts, TrioD1 triggers the formation of particular cell structures, similar to those elicited by RhoG, a GTPase known to activate both Rac1 and Cdc42Hs. In addition, the activity of TrioD1 requires the microtubule network and relocalizes RhoG at the active sites of the plasma membrane. Using a classical in vitro exchange assay, TrioD1 displays a higher GEF activity on RhoG than on Rac1. In fibroblasts, expression of dominant negative RhoG mutants totally abolished TrioD1 signaling, whereas dominant negative Rac1 and Cdc42Hs only led to partial and complementary inhibitions. Finally, expression of a Rho Binding Domain that specifically binds RhoG(GTP) led to the complete abolition of TrioD1 signaling, which strongly supports Rac1 not being activated by TrioD1 in vivo. These data demonstrate that Trio controls a signaling cascade that activates RhoG, which in turn activates Rac1 and Cdc42Hs.

Published
2000
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6. RhoG GTPase Controls a Pathway That Independently Activates Rac1 and Cdc42Hs

Author

Mayya Meriane, Emmanuel Vignal, Cécile Gauthier-Rouvière, Pierre Roux, Philippe Fort, Philippe Montcourier, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre de recherches de biochimie macromoléculaire (CRBM), Centre National de la Recherche Scientifique (CNRS)-IFR122-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Dynamique moléculaire des interactions membranaires (DMIM), Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 2 - Sciences et Techniques (UM2), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)

Subjects
rho GTP-Binding Proteins, MESH: 3T3 Cells, MESH: rac GTP-Binding Proteins, Cell Cycle Proteins, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Microtubules, GTP Phosphohydrolases, Mice, MESH: Animals, cdc42 GTP-Binding Protein, Cytoskeleton, Platelet-Derived Growth Factor, 0303 health sciences, biology, MESH: Microtubules, MESH: Platelet-Derived Growth Factor, 030302 biochemistry & molecular biology, MESH: Transcription Factors, 3T3 Cells, rac GTP-Binding Proteins, Cell biology, 3T3 Cells Actins/metabolism Animals Bradykinin/pharmacology Cell Cycle Proteins/*metabolism Cell Line Cytoskeleton/physiology GTP Phosphohydrolases/genetics/*metabolism GTP-Binding Proteins/*metabolism Green Fluorescent Proteins Luminescent Proteins/metabolism Mice Microtubules/metabolism Platelet-Derived Growth Factor/pharmacology Rats Recombinant Fusion Proteins/genetics/metabolism Transcription Factors/genetics/*metabolism cdc42 GTP-Binding Protein rac GTP-Binding Proteins, MESH: Luminescent Proteins, Lamellipodium, Filopodia, MESH: GTP Phosphohydrolases, MESH: GTP-Binding Proteins, MESH: Rats, Membrane ruffling, Recombinant Fusion Proteins, Green Fluorescent Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, RAC1, Rho family of GTPases, MESH: Actins, Bradykinin, Article, Cell Line, 03 medical and health sciences, MESH: Cell Cycle Proteins, MESH: Green Fluorescent Proteins, GTP-Binding Proteins, MESH: Cytoskeleton, MESH: Recombinant Fusion Proteins, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, Molecular Biology, 030304 developmental biology, MESH: Bradykinin, MESH: cdc42 GTP-Binding Protein, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Apical membrane, Actins, MESH: Cell Line, Rats, Luminescent Proteins, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, biology.protein, RhoG, Transcription Factors
Abstract

International audience; RhoG is a member of the Rho family of GTPases that shares 72% and 62% sequence identity with Rac1 and Cdc42Hs, respectively. We have expressed mutant RhoG proteins fused to the green fluorescent protein and analyzed subsequent changes in cell surface morphology and modifications of cytoskeletal structures. In rat and mouse fibroblasts, green fluorescent protein chimera and endogenous RhoG proteins colocalize according to a tubular cytoplasmic pattern, with perinuclear accumulation and local concentration at the plasma membrane. Constitutively active RhoG proteins produce morphological and cytoskeletal changes similar to those elicited by a simultaneous activation of Rac1 and Cdc42Hs, i.e., the formation of ruffles, lamellipodia, filopodia, and partial loss of stress fibers. In addition, RhoG and Cdc42Hs promote the formation of microvilli at the cell apical membrane. RhoG-dependent events are not mediated through a direct interaction with Rac1 and Cdc42Hs targets such as PAK-1, POR1, or WASP proteins but require endogenous Rac1 and Cdc42Hs activities: coexpression of a dominant negative Rac1 impairs membrane ruffling and lamellipodia but not filopodia or microvilli formation. Conversely, coexpression of a dominant negative Cdc42Hs only blocks microvilli and filopodia, but not membrane ruffling and lamellipodia. Microtubule depolymerization upon nocodazole treatment leads to a loss of RhoG protein from the cell periphery associated with a reversal of the RhoG phenotype, whereas PDGF or bradykinin stimulation of nocodazole-treated cells could still promote Rac1- and Cdc42Hs-dependent cytoskeletal reorganization. Therefore, our data demonstrate that RhoG controls a pathway that requires the microtubule network and activates Rac1 and Cdc42Hs independently of their growth factor signaling pathways.

Published
1998
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7. Solution structure of the antimicrobial peptide ranalexin and a study of its interaction with perdeuterated dodecylphosphocholine micelles

Author

Alain Chavanieu, André Aumelas, Gérard Grassy, Bernard Calas, Laurent Chiche, Philippe Roch, and Emmanuel Vignal

Subjects
Models, Molecular, Circular dichroism, Magnetic Resonance Spectroscopy, Protein Conformation, Stereochemistry, Phosphorylcholine, Molecular Sequence Data, Peptide, Peptides, Cyclic, Biochemistry, Micelle, Protein Structure, Secondary, chemistry.chemical_compound, Amide, Escherichia coli, Staphylococcus epidermidis, Animals, Organic chemistry, Amino Acid Sequence, Cysteine, Micelles, Skin, chemistry.chemical_classification, Rana catesbeiana, Chemistry, Circular Dichroism, Water, Biological activity, Trifluoroethanol, Deuterium, Antimicrobial, Anti-Bacterial Agents, Solutions, Helix, Oxidation-Reduction
Abstract

Ranalexin, a 20-residue peptide isolated from the skin of the bullfrog Rana catesbeiana displays antimicrobial activity. This peptide contains two cysteine residues in positions 14 and 20 linked by a disulphide bridge. Ranalexin was chemically synthesised and close antimicrobial activities were measured for the reduced and oxidised forms. The solution structure of ranalexin was determined by using circular dichroism, proton NMR spectroscopy and molecular modelling techniques. The reduced and oxidised forms of ranalexin are mainly unstructured in water but display an alpha-helical structure spanning residues 8-15 and 8-17, respectively, in a trifluoroethanol/water mixture (3:7, by vol.). Ranalexin was found to interact with micelles of dodecylphosphocholine and to adopt a similar helical structure. Moreover, slow-exchanging amide protons located on the same side of the helix suggest that the hydrophobic face of the helix lies on the micelle surface. Hydrophobic residues of the poorly structured N-terminal part which are important for the biological activity are also involved in the interaction with micelles. Taken together, the results suggest that the disulphide bond does not strongly affect either the conformation or the antimicrobial activity of ranalexin.

Published
1998
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8. MBNL1 and RBFOX2 cooperate to establish a splicing programme involved in pluripotent stem cell differentiation

Author

Jamal Tazi, Manuel Irimia, Panagiotis Prinos, Sherif Abou Elela, Pierre Roux, Julian P. Venables, Philippe Fort, Gilles Gadea, Philippe Thibault, Laure Lapasset, Jean-Marc Lemaitre, Roscoe Klinck, Benoit Chabot, Emmanuel Vignal, Institut de Génomique Fonctionnelle (IGF), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Processus Infectieux en Milieu Insulaire Tropical (PIMIT), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IRD-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Biologie Cellulaire (CRBM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Génomique Fonctionnelle, Université de Sherbrooke (UdeS), Centre Nationale de Recherche Scientifique, Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Université de Montpellier (UM), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-IRD-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR)

Subjects
RNA Splicing Factors, Mesoderm, Cellular differentiation, Induced Pluripotent Stem Cells, General Physics and Astronomy, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Gene Regulatory Networks, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Induced pluripotent stem cell, Cells, Cultured, 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, Gene Expression Profiling, Alternative splicing, Infant, Newborn, Gene Expression Regulation, Developmental, RNA-Binding Proteins, Cell Differentiation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, Fibroblasts, Cellular Reprogramming, Cell biology, Repressor Proteins, Gene expression profiling, Alternative Splicing, medicine.anatomical_structure, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, RNA splicing, Reprogramming, 030217 neurology & neurosurgery, Protein Binding, Signal Transduction
Abstract

International audience; Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) has provided huge insight into the pathways, mechanisms and transcription factors that control differentiation. Here we use high-throughput RT-PCR technology to take a snapshot of splicing changes in the full spectrum of high- and low-expressed genes during induction of fibroblasts, from several donors, into iPSCs and their subsequent redifferentiation. We uncover a programme of concerted alternative splicing changes involved in late mesoderm differentiation and controlled by key splicing regulators MBNL1 and RBFOX2. These critical splicing adjustments arise early in vertebrate evolution and remain fixed in at least 10 genes (including PLOD2, CLSTN1, ATP2A1, PALM, ITGA6, KIF13A, FMNL3, PPIP5K1, MARK2 and FNIP1), implying that vertebrates require alternative splicing to fully implement the instructions of transcriptional control networks.

Published
2013
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9. Applying ecological and evolutionary theory to cancer : a long and winding road

Author

Frédérique Billy, Annabelle Ballesta, Philippe Fort, Benoît Perthame, Serge Koscielny, Helene Trauchessec, Daniel Fisher, Céline Cosseau, Guillaume Mitta, Ruoping Tang, Patrice Lassus, W. Vainchenker, Christoph Grunau, Damien Grégoire, Corinne Quittau-Prévostel, Vjekoslav Dulic, Vitali Volpert, Eric Assenat, Michael E. Hochberg, Alexander Lorz, Philippe Blache, Thomas Lepoutre, François Delhommeau, Jean-Pierre Marie, Urszula Hibner, Peggy Raynaud, Frédéric Thomas, Jean Clairambault, Dorothée Missé, Fanny Fava, Eric Solary, Benjamin Roche, François Rousset, Emmanuel Vignal, Liliana Krasinska, Raphael Itzykson, Stephen Baghdiguian, Simon P. Daoust, Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Biologie Cellulaire (CRBM), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche sur l'Education, les apprentissages et la didactique (CREAD), Institut universitaire de formation des maîtres - Bretagne (IUFM Bretagne), Université de Brest (UBO)-Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-Université de Rennes 2 (UR2), Ecologie et évolution des interactions [2011-2014] (2EI), Université de Perpignan Via Domitia (UPVD)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), Service Médico-Chirurgical des Maladies de l'Appareil Digestif et de Transplantation Hépatique, Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire Jacques-Louis Lions (LJLL), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Nonlinear Analysis for Biology and Geophysical flows (BANG), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Inria Paris-Rocquencourt, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Université Paris Descartes - Paris 5 (UPD5), CIC Saint-Antoine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Mathématiques et Applications - ENS Paris (DMA), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Multi-scale modelling of cell dynamics : application to hematopoiesis (DRACULA), 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)-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), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), 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)-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), Institut Camille Jordan (ICJ), Laboratoire Parole et Langage (LPL), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), National Center for Ecological Analysis and Synthesis (NCEAS), Santa Fe Institute, Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle ( MIVEGEC ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD [France-Sud] ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ), Centre de recherches de biochimie macromoléculaire ( CRBM ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -IFR122-Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre de Recherche sur l'Education, les apprentissages et la didactique ( CREAD ), Institut universitaire de formation des maîtres - Bretagne ( IUFM Bretagne ), Université de Brest ( UBO ) -Université de Brest ( UBO ) -Université européenne de Bretagne ( UEB ) -Université de Rennes 2 ( UR2 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ), Ecologie et évolution des interactions ( 2EI ), Université de Perpignan Via Domitia ( UPVD ) -Centre National de la Recherche Scientifique ( CNRS ), Institut des Sciences de l'Evolution de Montpellier ( ISEM ), Université de Montpellier ( UM ) -Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique ( CNRS ), CHU Saint-Eloi, Laboratoire Jacques-Louis Lions ( LJLL ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Nonlinear Analysis for Biology and Geophysical flows ( BANG ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ) -Inria Paris-Rocquencourt, Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ), Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Saint-Antoine [APHP], Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Gustave Roussy ( IGR ) -Université Paris-Sud - Paris 11 ( UP11 ), Département de Mathématiques et Applications - ENS Paris ( DMA ), École normale supérieure - Paris ( ENS Paris ) -Centre National de la Recherche Scientifique ( CNRS ), Multi-scale modelling of cell dynamics : application to hematopoiesis ( DRACULA ), Institut Camille Jordan [Villeurbanne] ( ICJ ), Centre National de la Recherche Scientifique ( CNRS ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -École Centrale de Lyon ( ECL ), Université de Lyon-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 ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -École Centrale de Lyon ( ECL ), Université de Lyon-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 ), Université de Lyon, Laboratoire Parole et Langage ( LPL ), Centre National de la Recherche Scientifique ( CNRS ) -Aix Marseille Université ( AMU ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), National Center for Ecological Analysis and Synthesis ( NCEAS ), National Center for Ecological Analysis and Synthesis, Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE), École normale supérieure - Paris (ENS Paris), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-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 [Villeurbanne] (ICJ), Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Institut Camille Jordan [Villeurbanne] (ICJ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre de recherches de biochimie macromoléculaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-IFR122-Centre National de la Recherche Scientifique (CNRS), Ecologie et évolution des interactions (2EI), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [APHP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Jean Monnet [Saint-Étienne] (UJM)-École Centrale de Lyon (ECL), Université de Lyon-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)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Jean Monnet [Saint-Étienne] (UJM)-École Centrale de Lyon (ECL), 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 de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UR226, Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Laboratoire d'Ingénierie dirigée par les modèles pour les Systèmes Embarqués (LISE), Département Ingénierie Logiciels et Systèmes (DILS), Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Université Paris-Saclay-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Recherche pour le Développement (IRD [France-Sud])-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (CIRAD)-École pratique des hautes études (EPHE)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire d'Etudes Aérodynamiques (LEA), Centre National de la Recherche Scientifique (CNRS)-ENSMA-Université de Poitiers, Hématopoïèse normale et pathologique (U1170 Inserm), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Multi-Models and Numerical Methods (M3N), Inria Paris-Rocquencourt, Génétique et évolution des maladies infectieuses (GEMI), and Modat, Anne

Subjects
Process (engineering), cancer, disease biology, [SDV.CAN]Life Sciences [q-bio]/Cancer, disease biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Synthesis, 03 medical and health sciences, 0302 clinical medicine, Genetics, Neoplastic progression, medicine, cancer, evolutionary theory, ComputingMilieux_MISCELLANEOUS, Ecology, Evolution, Behavior and Systematics, Evolutionary theory, 030304 developmental biology, 0303 health sciences, [ SDE.BE ] Environmental Sciences/Biodiversity and Ecology, Ecology, Cancer, Evolutionary medicine, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Evasion (ethics), medicine.disease, 3. Good health, [SDE.BE] Environmental Sciences/Biodiversity and Ecology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, evolutionary medicine, 030220 oncology & carcinogenesis, Darwinism, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, General Agricultural and Biological Sciences
Abstract

International audience; Since the mid 1970s, cancer has been described as a process of Darwinian evolution, with somatic cellular selection and evolution being the fundamental processes leading to malignancy and its many manifestations (neoangiogenesis, evasion of the immune system, metastasis, and resistance to therapies). Historically, little attention has been placed on applications of evolutionary biology to understanding and controlling neoplastic progression and to prevent therapeutic failures. This is now beginning to change, and there is a growing international interest in the interface between cancer and evolutionary biology. The objective of this introduction is first to describe the basic ideas and concepts linking evolutionary biology to cancer. We then present four major fronts where the evolutionary perspective is most developed, namely laboratory and clinical models, mathematical models, databases, and techniques and assays. Finally, we discuss several of the most promising challenges and future prospects in this interdisciplinary research direction in the war against cancer.

Published
2013
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10. Tissue-Specific Alternative Splicing of Tak1 Is Conserved in Deuterostomes

Author

Philippe Fort, Jamal Tazi, Emmanuel Vignal, Julian P. Venables, Stephen Baghdiguian, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UR226, Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de recherches de biochimie macromoléculaire ( CRBM ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -IFR122-Centre National de la Recherche Scientifique ( CNRS ), Institut des Sciences de l'Evolution de Montpellier ( ISEM ), Université de Montpellier ( UM ) -Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique ( CNRS ), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS)

Subjects
Molecular Sequence Data, Sequence alignment, tissue specificity, FOX proteins, TGF beta signaling, Evolution, Molecular, 03 medical and health sciences, Splicing factor, Exon, Mice, Xenopus laevis, Transforming Growth Factor beta, evolution, Genetics, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Ambulacraria, Molecular Biology, Gene, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Mammals, 0303 health sciences, biology, Muscles, Myocardium, 030302 biochemistry & molecular biology, Alternative splicing, Fishes, Exons, biology.organism_classification, MAP Kinase Kinase Kinases, Cell biology, Isoenzymes, Organ Specificity, Sea Urchins, RNA splicing, Sequence Alignment
Abstract

International audience; Alternative splicing allows organisms to rapidly modulate protein functions to physiological changes and therefore represents a highly versatile adaptive process. We investigated the conservation of the evolutionary history of the "Fox" family of RNA-binding splicing factors (RBFOX) as well as the conservation of regulated alternative splicing of the genes they control. We found that the RBFOX proteins are conserved in all metazoans examined. In humans, Fox proteins control muscle-specific alternative splicing of many genes but despite the conservation of splicing factors, conservation of regulation of alternative splicing has never been demonstrated between man and nonvertebrate species. Therefore, we studied 40 known Fox-regulated human exons and found that 22 had a tissue-specific splicing pattern in muscle and heart. Of these, 11 were spliced in the same tissue-specific manner in mouse tissues and 4 were tissue-specifically spliced in muscle and heart of the frog Xenopus laevis. The inclusion of two of these alternative exons was also downregulated during tadpole development. Of the 40 in the starting set, the most conserved alternative splicing event was in the transforming growth factor (TGF) beta-activated kinase Tak1 (MAP3K7) as this was also muscle specific in urochordates and in Ambulacraria, the most ancient deuterostome clade. We found exclusion of the muscle-specific exon of Tak1 was itself under control of TGF beta in cell culture and consistently that TGF beta caused an upregulation of Fox2 (RBFOX2) expression. The alternative exon, which codes for an in-frame 27 amino acids between the kinase and known regulatory domain of TAK1, contains conserved features in all organisms including potential phosphorylation sites and likely has an important conserved function in TGF beta signaling and development. This study establishes that deuterostomes share a remarkable conserved physiological process that involves a splicing factor and expression of tissue-specific isoforms of a target gene that expedites a highly conserved signaling pathway.

Published
2012
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11. Activity of the RhoU/Wrch1 GTPase is critical for cranial neural crest cell migration

Author

Sandrine Faure, Pascal de Santa Barbara, Cécile Notarnicola, Linda Guémar, Nathalie Morin, Philippe Fort, Emmanuel Vignal, Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Muscle et pathologies, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherches de biochimie macromoléculaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-IFR122-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherches sur les Herbivores - UMR 1213 (UMRH), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Dubois, Frederic

Subjects
rho GTP-Binding Proteins, Xenopus, Cell, Ectoderm, MESH: rac GTP-Binding Proteins, Chick Embryo, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Xenopus Proteins, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Xenopus laevis, 0302 clinical medicine, Cranial neural crest, Cell Movement, Rho GTPases, MESH: Animals, RhoU, MESH: Cell Movement, MESH: Xenopus Proteins, Migration, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, education.field_of_study, Wnt signaling pathway, Cell Polarity, Neural crest, Cell migration, MESH: Chick Embryo, rac GTP-Binding Proteins, Cell biology, medicine.anatomical_structure, Neural Crest, MESH: Cell Polarity, MESH: Focal Adhesion Kinase 2, MESH: p21-Activated Kinases, Population, RAC1, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, MESH: Xenopus laevis, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, education, Molecular Biology, 030304 developmental biology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, MESH: rho GTP-Binding Proteins, MESH: Neural Crest, Focal Adhesion Kinase 2, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, p21-Activated Kinases, 030217 neurology & neurosurgery, Developmental Biology
Abstract

International audience; The neural crest (NC) is a stem cell-like population that arises at the border of neural and non-neural ectoderm. During development, NC undergoes an epithelio-mesenchymal transition (EMT), i.e. loss of epithelial junctions and acquisition of pro-migratory properties, invades the entire embryo and differentiates into a wide diversity of terminal tissues. We have studied the implication of Rho pathways in NC development and previously showed that RhoV is required for cranial neural crest (CNC) cell specification. We show here that the non-canonical Wnt response rhoU/wrch1 gene, closely related to rhoV, is also expressed in CNC cells but at later stages. Using both gain- and loss-of-function experiments, we demonstrate that the level of RhoU expression is critical for CNC cell migration and subsequent differentiation into craniofacial cartilages. In in vitro cultures, RhoU activates pathways that cooperate with PAK1 and Rac1 in epithelial adhesion, cell spreading and directional cell migration. These data support the conclusion that RhoU is an essential regulator of CNC cell migration.

Published
2011
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12. A cell active chemical GEF inhibitor selectively targets the Trio/RhoG/Rac1 signaling pathway

Author

Sophie Charrasse, Anne Blangy, Emmanuel Vignal, Philippe Fort, Susanne Schmidt, Mylène Weill, Jean-Paul Leonetti, Nathalie Bouquier, Centre de recherche en Biologie Cellulaire (CRBM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), Réplication virale, pathogenèse et immunité, Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche en Infectiologie de Montpellier (IRIM), Pasqualini, Nathalie, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Centre de recherches de biochimie macromoléculaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-IFR122-Centre National de la Recherche Scientifique (CNRS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (CIRAD)-École pratique des hautes études (EPHE)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UR226

Subjects
rac1 GTP-Binding Protein, rho GTP-Binding Proteins, MESH: Signal Transduction, RHOA, Cellular differentiation, Clinical Biochemistry, GTPase, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, PC12 Cells, Biochemistry, Mice, MESH: Protein Structure, Tertiary, 0302 clinical medicine, Cell Movement, Drug Discovery, Guanine Nucleotide Exchange Factors, MESH: Guanine Nucleotide Exchange Factors, MESH: Animals, MESH: Cell Movement, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, biology, MESH: Kinetics, Cell Differentiation, General Medicine, Cell biology, SIGNALING, 030220 oncology & carcinogenesis, Molecular Medicine, Guanine nucleotide exchange factor, Signal transduction, Signal Transduction, MESH: Cell Differentiation, Membrane ruffling, MESH: Rats, MESH: Thiazoles, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Line, 03 medical and health sciences, Neurites, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, MESH: PC12 Cells, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cell adhesion, Molecular Biology, MESH: Mice, Nitrobenzenes, 030304 developmental biology, Pharmacology, MESH: Humans, MESH: rac1 GTP-Binding Protein, MESH: Nitrobenzenes, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: rho GTP-Binding Proteins, MESH: Neurites, Protein Structure, Tertiary, Rats, MESH: Cell Line, Kinetics, Thiazoles, CHEMBIO, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, biology.protein, Benzimidazoles, CELLBIO, RhoG, MESH: Benzimidazoles
Abstract

SummaryRhoGEFs (guanine nucleotide exchange factors of the Rho GTPase family) are upstream regulators of cell adhesion and migration pathways, thus representing attractive yet relatively unexplored targets for the development of anti-invasive drugs. We screened for chemical inhibitors of TrioN, the N-terminal GEF domain of the multidomain Trio protein, and identified ITX3 as a nontoxic inhibitor. In transfected mammalian cells, ITX3 blocked TrioN-mediated dorsal membrane ruffling and Rac1 activation while having no effect on GEF337-, Tiam1-, or Vav2-mediated RhoA or Rac1 activation. ITX3 specifically inhibited endogenous TrioN activity, as evidenced by its ability to inhibit neurite outgrowth in nerve growth factor (NGF)–stimulated PC12 cells or C2C12 differentiation into myotubes. This study introduces a selective cell active inhibitor of the Trio/RhoG/Rac1 pathway and validates RhoGEFs as druggable targets.

Published
2009
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13. Expression of RhoB in the developing Xenopus laevis embryo

Author

Sandrine Faure, Jean Marc Donnay, Pascal de Santa Barbara, Linda Guémar, Philippe Fort, Emmanuel Vignal, Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Muscle et pathologies, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherches de biochimie macromoléculaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-IFR122-Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherches sur les Herbivores - UMR 1213 (UMRH), and VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)

Subjects
animal structures, Embryo, Nonmammalian, RHOB, Molecular Sequence Data, Xenopus, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], In situ hybridization, Biology, Xenopus Proteins, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Cell morphology, 03 medical and health sciences, Xenopus laevis, 0302 clinical medicine, Genetics, Paraxial mesoderm, Animals, Amino Acid Sequence, rhoB GTP-Binding Protein, Molecular Biology, ComputingMilieux_MISCELLANEOUS, In Situ Hybridization, Phylogeny, 030304 developmental biology, Expressed Sequence Tags, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, Neural crest, Gene Expression Regulation, Developmental, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Embryo, biology.organism_classification, Molecular biology, Cell biology, Gastrulation, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, 030220 oncology & carcinogenesis, embryonic structures, Sequence Alignment, Developmental Biology
Abstract

Rho GTPases are signaling components that participate to the control of cell morphology, adhesion and motility through the regulation of F-actin cytoskeleton dynamics. In this paper, we report the identification of RhoB in Xenopus laevis (XRhoB) and its expression pattern during early development. Whole-mount in situ hybridization analysis indicated that XrhoB is expressed at high levels in the dorsal marginal zone early in gastrula and in the dorsal midline at later stages. At mid-neurula stages, XrhoB expression extends to the central nervous system, presomitic mesoderm and somites. Later during development, rhoB mRNA is detected in the eyes, the migrating neural crest cells as well as the dorso-lateral part of the somites.

Published
2006
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14. Resources

Author

José M.A. Moreira and Emmanuel Vignal

Subjects
World Wide Web, Engineering, Resource (project management), Science research, Point (typography), business.industry, Subject (documents), The Internet, Instrumentation (computer programming), Isolation (database systems), business, Authentication (law)
Abstract

Publisher Summary This chapter presents a list of various websites from where researchers can collect useful information related to their research work. Cell biologists can tap into the website of the World Federation for Culture Collections (WFCC). The WFCC is a federation concerned with the collection, authentication, maintenance, and distribution of cultures of microorganisms and cultured cells. The RIKEN cell bank has been organized as a unique, nonprofit public collection for deposit, isolation, preservation, and distribution of cultured animal cell lines produced by the life science research community. A website for the Antibody Resource Page provides a broad collection of links to companies that sell antibodies or antibody-related products on the internet. KabatMan site provides information on antibody structure and sequence as well as other useful links. Flow Cytometry on the Website is a collection of links for those interested in flow cytometry. A good starting point if one is looking for software protocols, instrumentation protocols, or any flow cytometry-related subject.

Published
2006
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16. Calponin repeats regulate actin filament stability and formation of podosomes in smooth muscle cells

Author

Gerald Burgstaller, Guenter P. Resch, Irina Kaverina, Emmanuel Vignal, and Mario Gimona

Subjects
Organelles, biology, Calcium-Binding Proteins, Microfilament Proteins, Myocytes, Smooth Muscle, Actin remodeling, Arp2/3 complex, Fluorescent Antibody Technique, Cell Biology, macromolecular substances, Articles, Actin cytoskeleton, Actins, Cell biology, Rats, Actin remodeling of neurons, Actin Cytoskeleton, Microscopy, Electron, Profilin, biology.protein, Animals, MDia1, Actin-binding protein, Cytoskeleton, Molecular Biology
Abstract

Phorbol ester induces actin cytoskeleton rearrangements in cultured vascular smooth muscle cells. Calponin and SM22 α are major components of differentiated smooth muscle and potential regulators of actin cytoskeleton interactions. Here we show that actin fibers decorated with h1 CaP remain stable, whereas SM22 α-decorated actin bundles undergo rapid reorganization into podosomes within 30 min of PDBu exposure. Ectopic expression of GFP α-actinin had no effect on the stability of the actin cytoskeleton and α-actinin was transported rapidly into PDBu-induced podosomes. Our results demonstrate the involvement of CaP and SM22 α in coordinating the balance between stabilization and dynamics of the actin cytoskeleton in mammalian smooth muscle. We provide evidence for the existence of two functionally distinct actin filament populations and introduce a molecular mechanism for the stabilization of the actin cytoskeleton by the unique actin-binding interface formed by calponin family-specific CLIK23repeats.

Published
2003

18. The lamellipodium: where motility begins

Author

Emmanuel Vignal, Klemens Rottner, J. Victor Small, and Theresia E. B. Stradal

Subjects
rho GTP-Binding Proteins, biology, Macromolecular Substances, Molecular Motor Proteins, Arp2/3 complex, Actin remodeling, Proteins, macromolecular substances, Cell Biology, Actin cytoskeleton, Actins, Cell biology, Cell Movement, Myosin, biology.protein, Animals, Pseudopodia, Lamellipodium, Cytoskeleton, Filopodia, Actin, Signal Transduction
Abstract

Lamellipodia, filopodia and membrane ruffles are essential for cell motility, the organization of membrane domains, phagocytosis and the development of substrate adhesions. Their formation relies on the regulated recruitment of molecular scaffolds to their tips (to harness and localize actin polymerization), coupled to the coordinated organization of actin filaments into lamella networks and bundled arrays. Their turnover requires further molecular complexes for the disassembly and recycling of lamellipodium components. Here, we give a spatial inventory of the many molecular players in this dynamic domain of the actin cytoskeleton in order to highlight the open questions and the challenges ahead.

Published
2002

19. Kinectin Is a Key Effector of RhoG Microtubule-Dependent Cellular Activity

Author

Anne Blangy, M. Martin, Philippe Fort, Emmanuel Vignal, Cécile Gauthier-Rouvière, Centre de recherches de biochimie macromoléculaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-IFR122-Centre National de la Recherche Scientifique (CNRS), Laboratoire des technologies de la microélectronique (LTM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), inconnu, Inconnu, Centre National de la Recherche Scientifique (CNRS), and Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
rac1 GTP-Binding Protein, rho GTP-Binding Proteins, RHOA, Gene Expression, Kinesins, CDC42, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Endoplasmic Reticulum, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Microtubules, GTP Phosphohydrolases, Jurkat Cells, 0302 clinical medicine, cdc42 GTP-Binding Protein, Cell Growth and Development, Cytoskeleton, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Microscopy, Video, biology, Blood Proteins, 3. Good health, Cell biology, Phenotype, Cdc42 GTP-Binding Protein, COS Cells, Kinesin, Protein Binding, Lysosomal transport, Rho family of GTPases, [SDV.CAN]Life Sciences [q-bio]/Cancer, Transfection, 03 medical and health sciences, Microtubule, Two-Hybrid System Techniques, Animals, Humans, Antibodies, Blocking, Molecular Biology, 030304 developmental biology, Membrane Proteins, Biological Transport, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Fibroblasts, Protein Structure, Tertiary, Rats, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, biology.protein, RhoG, Lysosomes, rhoA GTP-Binding Protein, 030217 neurology & neurosurgery
Abstract

RhoG is a member of the Rho family of GTPases that activates Rac1 and Cdc42 through a microtubule-dependent pathway. To gain understanding of RhoG downstream signaling, we performed a yeast two-hybrid screen from which we identified kinectin, a 156-kDa protein that binds in vitro to conventional kinesin and enhances microtubule-dependent kinesin ATPase activity. We show that RhoG(GTP) specifically interacts with the central domain of kinectin, which also contains a RhoA binding domain in its C terminus. Interaction was confirmed by coprecipitation of kinectin with active RhoG(G12V) in COS-7 cells. RhoG, kinectin, and kinesin colocalize in REF-52 and COS-7 cells, mainly in the endoplasmic reticulum but also in lysosomes. Kinectin distribution in REF-52 cells is modulated according to endogenous RhoG activity. In addition, by using injection of anti-kinectin antibodies that challenge RhoG-kinectin interaction or by blocking anti-kinesin antibodies, we show that RhoG morphogenic activity relies on kinectin interaction and kinesin activity. Finally, kinectin overexpression elicits Rac1- and Cdc42-dependent cytoskeletal effects and switches cells to a RhoA phenotype when RhoG activity is inhibited or microtubules are disrupted. The functional links among RhoG, kinectin, and kinesin are further supported by time-lapse videomicroscopy of COS-7 cells, which showed that the microtubule-dependent lysosomal transport is facilitated by RhoG activation or kinectin overexpression and is severely stemmed upon RhoG inhibition. These data establish that kinectin is a key mediator of microtubule-dependent RhoG activity and suggest that kinectin also mediates RhoG- and RhoA-dependent antagonistic pathways.

Published
2001
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20. Characterization of TCL, a new GTPase of the rho family related to TC10 andCcdc42

Author

Anne Blangy, Marion de Toledo, Philippe Fort, Cécile Gauthier-Rouvière, Angela Ladopoulou, Franck Comunale, Emmanuel Vignal, Centre de recherches de biochimie macromoléculaire (CRBM), and Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-IFR122-Centre National de la Recherche Scientifique (CNRS)

Subjects
rho GTP-Binding Proteins, GTP', Mutant, CDC42, GTPase, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Cell morphology, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Biochemistry, GTP Phosphohydrolases, Cell membrane, Mice, 0302 clinical medicine, cdc42 GTP-Binding Protein, Cytoskeleton, Genetics, 0303 health sciences, Immunohistochemistry, 3. Good health, Cell biology, medicine.anatomical_structure, Organ Specificity, 030220 oncology & carcinogenesis, Wiskott-Aldrich Syndrome Protein, Protein Binding, Recombinant Fusion Proteins, Molecular Sequence Data, RAC1, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Protein Serine-Threonine Kinases, Cell Line, 03 medical and health sciences, Two-Hybrid System Techniques, medicine, Animals, Humans, Amino Acid Sequence, RNA, Messenger, Molecular Biology, 030304 developmental biology, Cell Size, Messenger RNA, Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Actins, Protein Structure, Tertiary, Rats, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, p21-Activated Kinases, Mutation, Microscopy, Electron, Scanning, Sequence Alignment
Abstract

International audience; GTPases of the Rho family control a wide variety of cellular processes such as cell morphology, motility, proliferation, differentiation, and apoptosis. We report here the characterization of a new Rho member, which shares 85% and 78% amino acid similarity to TC10 and Cdc42, respectively. This GTPase, termed as TC10-like (TCL) is encoded by an unexpectedly large locus, made of five exons spanning over 85 kilobases on human chromosome 14. TCL mRNA is 2.5 kilobases long and is mainly expressed in heart. In vitro, TCL shows rapid GDP/GTP exchange and displays higher GTP dissocia-tion and hydolysis rates than TC10. Using the yeast two-hybrid system and GST pull-down assays, we show that GTP-bound but not GDP-bound TCL protein directly interacts with Cdc42/Rac interacting binding domains, such as those found in PAK and WASP. Despite its overall similarity to TC10 and Cdc42, the constitutively active TCL mutant displays distinct morphogenic activity in REF-52 fibroblasts, producing large and dynamic F-actin-rich ruffles on the dorsal cell membrane. Interestingly , TCL morphogenic activity is blocked by dominant negative Rac1 and Cdc42 mutants, suggesting a cross-talk between these three Rho GTPases.

Published
2000
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22. Calponin repeats regulate actin filament stability and formation of podosomes in smooth muscle cells.

Author

Mario, Gimona, Irina, Kaverina, P, Resch Guenter, Emmanuel, Vignal, and Gerald, Burgstaller

Abstract

Phorbol ester induces actin cytoskeleton rearrangements in cultured vascular smooth muscle cells. Calponin and SM22 alpha are major components of differentiated smooth muscle and potential regulators of actin cytoskeleton interactions. Here we show that actin fibers decorated with h1 CaP remain stable, whereas SM22 alpha-decorated actin bundles undergo rapid reorganization into podosomes within 30 min of PDBu exposure. Ectopic expression of GFP alpha-actinin had no effect on the stability of the actin cytoskeleton and alpha-actinin was transported rapidly into PDBu-induced podosomes. Our results demonstrate the involvement of CaP and SM22 alpha in coordinating the balance between stabilization and dynamics of the actin cytoskeleton in mammalian smooth muscle. We provide evidence for the existence of two functionally distinct actin filament populations and introduce a molecular mechanism for the stabilization of the actin cytoskeleton by the unique actin-binding interface formed by calponin family-specific CLIK23 repeats.

Published
2003

23. Signaling networks of Rho GTPases

Author

Emmanuel Vignal, Anne Blangy, Philippe Fort, Centre de recherches de biochimie macromoléculaire (CRBM), and Centre National de la Recherche Scientifique (CNRS)-IFR122-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1)

Subjects
health care facilities, manpower, and services, [SDV]Life Sciences [q-bio], education, humanities, health care economics and organizations
Abstract

Journal Abbreviation: Rho GTPases; International audience

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