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2. Differential expression of paralog RNA binding proteins establishes a dynamic splicing program required for normal cerebral cortex development

Author

Cesari, Eleonora, Farini, Donatella, Medici, Vanessa, Ehrmann, Ingrid, Guerra, Marika, Testa, Erika, Naro, Chiara, Geloso, Maria Concetta, Pagliarini, Vittoria, LA BARBERA, Livia, D'Amelio, Marcello, Orsini, Tiziana, FARIOLI VECCHIOLI, Stefano, Tamagnone, Luca, Fort, Philippe, Viscomi, Maria Teresa, Elliott, David, Sette, Claudio, ELEONORA CESARI, MARIKA GUERRA, ERIKA TESTA, CHIARA NARO (ORCID:0000-0002-3135-3218), MARIA CONCETTA GELOSO (ORCID:0000-0002-0622-9813), VITTORIA PAGLIARINI (ORCID:0000-0002-2388-0675), L TAMAGNONE (ORCID:0000-0002-2884-7946), MARIA TERESA VISCOMI (ORCID:0000-0002-9096-4967), CLAUDIO SETTE (ORCID:0000-0003-2864-8266), Cesari, Eleonora, Farini, Donatella, Medici, Vanessa, Ehrmann, Ingrid, Guerra, Marika, Testa, Erika, Naro, Chiara, Geloso, Maria Concetta, Pagliarini, Vittoria, LA BARBERA, Livia, D'Amelio, Marcello, Orsini, Tiziana, FARIOLI VECCHIOLI, Stefano, Tamagnone, Luca, Fort, Philippe, Viscomi, Maria Teresa, Elliott, David, Sette, Claudio, ELEONORA CESARI, MARIKA GUERRA, ERIKA TESTA, CHIARA NARO (ORCID:0000-0002-3135-3218), MARIA CONCETTA GELOSO (ORCID:0000-0002-0622-9813), VITTORIA PAGLIARINI (ORCID:0000-0002-2388-0675), L TAMAGNONE (ORCID:0000-0002-2884-7946), MARIA TERESA VISCOMI (ORCID:0000-0002-9096-4967), and CLAUDIO SETTE (ORCID:0000-0003-2864-8266)

Abstract

Sam68 and SLM2 are paralog RNA binding proteins (RBPs) expressed in the cerebral cortex and display similar splicing activities. However, their relative functions during cortical development are unknown. We found that these RBPs exhibit an opposite expression pattern during development. Sam68 expression declines postnatally while SLM2 increases after birth, and this developmental pattern is reinforced by hierarchical control of Sam68 expression by SLM2. Analysis of Sam68:Slm2 double knockout (Sam68:Slm2dko) mice revealed hundreds of exons that respond to joint depletion of these proteins. Moreover, parallel analysis of single and double knockout cortices indicated that exons regulated mainly by SLM2 are characterized by a dynamic splicing pattern during development, whereas Sam68-dependent exons are spliced at relatively constant rates. Dynamic splicing of SLM2-sensitive exons is completely suppressed in the Sam68:Slm2dko developing cortex. Sam68:Slm2dko mice die perinatally with defects in neurogenesis and in neuronal differentiation, and develop a hydrocephalus, consistent with splicing alterations in genes related to these biological processes. Thus, our study reveals that developmental control of separate Sam68 and Slm2 paralog genes encoding homologous RBPs enables the orchestration of a dynamic splicing program needed for brain development and viability, while ensuring a robust redundant mechanism that supports proper cortical development.

Published
2024

3. Differential expression of paralog RNA binding proteins establishes a dynamic splicing program required for normal cerebral cortex development

Author

Cesari, Eleonora, primary, Farini, Donatella, additional, Medici, Vanessa, additional, Ehrmann, Ingrid, additional, Guerra, Marika, additional, Testa, Erika, additional, Naro, Chiara, additional, Geloso, Maria Concetta, additional, Pagliarini, Vittoria, additional, La Barbera, Livia, additional, D’Amelio, Marcello, additional, Orsini, Tiziana, additional, Vecchioli, Stefano Farioli, additional, Tamagnone, Luca, additional, Fort, Philippe, additional, Viscomi, Maria Teresa, additional, Elliott, David J, additional, and Sette, Claudio, additional

Published
2024
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5. PIP30/FAM192A is a novel regulator of the nuclear proteasome activator PA28γ

Author

Jonik-Nowak, Beata, Menneteau, Thomas, Fesquet, Didier, Baldin, Véronique, Bonne-Andrea, Catherine, Méchali, Francisca, Fabre, Bertrand, Boisguerin, Prisca, de Rossi, Sylvain, Henriquet, Corinne, Pugnière, Martine, Ducoux-Petit, Manuelle, Burlet-Schiltz, Odile, Lamond, Angus I., Fort, Philippe, Boulon, Séverine, Bousquet, Marie-Pierre, and Coux, Olivier

Published
2018

8. Ras/MAPK signalling intensity defines subclonal fitness in a mouse model of hepatocellular carcinoma

Author

Lozano, Anthony, primary, Souche, Francois-Régis, additional, Chavey, Carine, additional, Dardalhon, Valérie, additional, Ramirez, Christel, additional, Vegna, Serena, additional, Desandre, Guillaume, additional, Riviere, Anaïs, additional, Zine El Aabidine, Amal, additional, Fort, Philippe, additional, Akkari, Leila, additional, Hibner, Urszula, additional, and Grégoire, Damien, additional

Published
2023
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10. Author response: Ras/MAPK signalling intensity defines subclonal fitness in a mouse model of hepatocellular carcinoma

Author

Lozano, Anthony, primary, Souche, Francois-Régis, additional, Chavey, Carine, additional, Dardalhon, Valérie, additional, Ramirez, Christel, additional, Vegna, Serena, additional, Desandre, Guillaume, additional, Riviere, Anaïs, additional, Zine El Aabidine, Amal, additional, Fort, Philippe, additional, Akkari, Leila, additional, Hibner, Urszula, additional, and Grégoire, Damien, additional

Published
2022
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13. SHED-Dependent Oncogenic Signaling of the PEAK3 Pseudo-Kinase

Author

Ounoughene, Youcef, primary, Fourgous, Elise, additional, Boublik, Yvan, additional, Saland, Estelle, additional, Guiraud, Nathan, additional, Recher, Christian, additional, Urbach, Serge, additional, Fort, Philippe, additional, Sarry, Jean-Emmanuel, additional, Fesquet, Didier, additional, and Roche, Serge, additional

Published
2021
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14. Author Reply to Peer Reviews of Ras/MAPK signalling intensity defines subclonal fitness in a mouse model of primary and metastatic hepatocellular carcinoma

Author

Grégoire, Damien, primary, Hibner, Urszula, additional, Akkari, Leila, additional, Fort, Philippe, additional, El Aabidine, Amal Zine, additional, Dardalhon, Valérie, additional, Riviere, Anaïs, additional, Desandré, Guillaume, additional, Vegna, Serena, additional, Ramirez, Christel, additional, Souche, François-Régis, additional, and Lozano, Anthony, additional

Published
2021
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17. Ras/MAPK signalling intensity defines subclonal fitness in a mouse model of primary and metastatic hepatocellular carcinoma

Author

Lozano, Anthony, primary, Souche, François-Régis, additional, Ramirez, Christel, additional, Vegna, Serena, additional, Desandré, Guillaume, additional, Riviere, Anaïs, additional, Dardalhon, Valérie, additional, El Aabidine, Amal Zine, additional, Fort, Philippe, additional, Akkari, Leila, additional, Hibner, Urszula, additional, and Grégoire, Damien, additional

Published
2021
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18. Regulation of Src tumor activity by its N-terminal intrinsically disordered region

Author

Aponte, Emilie, primary, Lafitte, Marie, additional, Sirvent, Audrey, additional, Simon, Valérie, additional, Barbery, Maud, additional, Fourgous, Elise, additional, Maffei, Mariano, additional, Armand, Florence, additional, Hamelin, Romain, additional, Pannequin, Julie, additional, Fort, Philippe, additional, Pons, Miquel, additional, and Roche, Serge, additional

Published
2021
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19. The small GTPase RhoV is an essential regulator of neural crest induction in Xenopus

Author

Guemar, Linda, Barbara, Pascal De Santa, Vignal, Emmanuel, Maurel, Benjamin, Fort, Philippe, and Faure, Sandrine

Subjects
Knowledge-based system, Biological sciences
Abstract

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2007.07.031 Byline: Linda Guemar (a), Pascal de Santa Barbara (b), Emmanuel Vignal (a), Benjamin Maurel (a), Philippe Fort (a), Sandrine Faure (a) Keywords: Rho GTPases; RhoV; Cranial neural crest; Specification; Xenopus Abstract: In vertebrates, the Rho family of GTPases is made of 20 members which regulate a variety of cellular functions, including actin cytoskeleton dynamics, cell adhesion and motility, cell growth and survival, gene transcription and membrane trafficking. To get a comprehensive view of Rho implication in physiological epithelial-mesenchymal transition, we carried out an in situ hybridization-based screen to identify Rho members expressed in Xenopus neural crest cells, in which we previously reported RhoB expression at the migrating stage. In the present study, we identify RhoV as an early expressed neural crest marker and provide evidence that its activity is essential for neural crest cell induction. RhoV mRNA is maternally expressed and accumulates shortly after gastrulation in the neural crest forming region. Using antisense morpholino injection, we show that at neurula stages, RhoV depletion impairs expression of the neural crest markers Sox9, Slug or Twist but has no effect on Snail induction. At the tailbud stage, RhoV knockdown causes a dramatic loss of cranial neural crest derived structures. All these defects are rescued by ectopic wild-type RhoV, whose overexpression on its own expands the neural crest territory. Our findings disclose an unprecedented Rho function in pathways that control neural crest cells specification. Author Affiliation: (a) Centre de Recherches en Biochimie Macromoleculaire, UMR 5237 CNRS, 1919 route de Mende, 34293 Montpellier, France (b) INSERM, ERI 25, 'Muscle and Pathologies', 34295 Montpellier, France Article History: Received 30 March 2007; Revised 6 July 2007; Accepted 23 July 2007

Published
2007

20. Variability and expression of ankyrin domain genes in Wolbachia variants infecting the mosquito Culex pipiens

Author

Duron, Olivier, Boureux, Anthony, Echaubard, Pierre, Berthomieu, Arnaud, Berticat, Claire, Fort, Philippe, and Weill, Mylene

Subjects
Gene expression -- Research, Genetic variation -- Research, Wolbachia -- Genetic aspects, Wolbachia -- Research, Cytoplasmic inheritance -- Research, Biological sciences
Abstract

Wolbachia strains are maternally inherited endosymbiotic bacteria that infect many arthropod species and have evolved several different ways of manipulating their hosts, the most frequent way being cytoplasmic incompatibility (CI). CI leads to embryo death in crosses between infected males and uninfected females as well as in crosses between individuals infected by incompatible Wolbachia strains. The mosquito Culex pipiens exhibits the highest crossing type variability reported so far. Our crossing data support the notion that CI might be driven by at least two distinct genetic units that control the CI functions independently in males and females. Although the molecular basis of CI remains unknown, proteins with ankyrin (ANK) domains represent promising candidates since they might interact with a wide range of host proteins. Here we searched for sequence variability in the 58 ANK genes carried in the genomes of Wolbachia variants infecting Culexpipiens. Only five ANK genes were polymorphic in the genomes of incompatible Wolbachia variants, and none correlated with the CI pattern obtained with 15 mosquito strains (representing 14 Wolbachia variants). Further analysis of ANK gene expression evidenced host- and sex-dependent variations, which did not improve the correlation. Taken together, these data do not support the direct implication of ANK genes in CI determinism.

Published
2007

22. Fertilization regulates apoptosis of Ciona intestinalis extra-embryonic cells through thyroxine (T4)-dependent NF- [kappa]B pathway activation during early embryonic development

Author

Maury, Benoit, Martinand-Mari, Camille, Chambon, Jean-Philippe, Soule, Jonathan, Degols, Genevieve, Sahuquet, Alain, Weill, Mylene, Berthomieu, Arnaud, Fort, Philippe, Mangeat, Paul, and Baghdiguian, Stephen

Subjects
Apoptosis -- Research, Thyroxine -- Research, Cellular signal transduction -- Research, Fertilization (Biology) -- Research, Ascidiacea -- Research, Biological sciences
Abstract

The role of a fertilization signal in controlling apoptosis of extra-embryonic cells, using thyroxine (T4)-dependent NF- [kappa]B pathway during embryonic development of Ciona intestinalis, is studied.

Published
2006

23. NOPCHAP1 is a PAQosome cofactor that helps loading NOP58 on RUVBL1/2 during box C/D snoRNP biogenesis

Author

Abel, Yoann, primary, Paiva, Ana C F, additional, Bizarro, Jonathan, additional, Chagot, Marie-Eve, additional, Santo, Paulo E, additional, Robert, Marie-Cécile, additional, Quinternet, Marc, additional, Vandermoere, Franck, additional, Sousa, Pedro M F, additional, Fort, Philippe, additional, Charpentier, Bruno, additional, Manival, Xavier, additional, Bandeiras, Tiago M, additional, Bertrand, Edouard, additional, and Verheggen, Céline, additional

Published
2020
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27. Aspartate‐phobia of thermophiles as a reaction to deleterious chemical transformations.

Author

Villain, Etienne, Fort, Philippe, and Kajava, Andrey V

Subjects
*CHEMICAL amplification, *CHEMICAL reactions, *HIGH temperatures, *ASPARTIC acid, *PROTEIN conformation, *STATISTICS
Abstract

Prokaryotes growing at high temperatures have a high proportion of charged residues in their proteins to stabilize their 3D structure. By mining 175 disparate bacterial and archaeal proteomes we found that, against the general trend for charged residues, the frequency of aspartic acid residues decreases strongly as natural growth temperature increases. In search of the explanation, we hypothesized that the reason for such unusual correlation is the deleterious consequences of spontaneous chemical transformations of aspartate at high temperatures. Our subsequent statistical analysis supported this hypothesis. This finding reveals that organisms have likely adapted to high temperatures by minimizing the harmful consequences of spontaneous chemical transformations. [ABSTRACT FROM AUTHOR]

Published
2022
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33. The Evolutionary Landscape of Dbl-Like RhoGEF Families: Adapting Eukaryotic Cells to Environmental Signals

Author

Fort, Philippe, Blangy, Anne, Centre de recherche en Biologie Cellulaire (CRBM), and Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)

Subjects
Dbl, Adaptation, Biological, Fungi, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [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, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Evolution, Molecular, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Eukaryotic Cells, Rho GTPases, Vertebrates, cell signaling, Animals, Humans, Metagenomics, guanine nucleotide exchange factors, Phylogeny, Rho Guanine Nucleotide Exchange Factors, Research Article, Signal Transduction
Abstract

International audience; The dynamics of cell morphology in eukaryotes is largely controlled by small GTPases of the Rho family. Rho GTPases are activated by guanine nucleotide exchange factors (RhoGEFs), of which diffuse B-cell lymphoma (Dbl)-like members form the largest family. Here, we surveyed Dbl-like sequences from 175 eukaryotic genomes and illuminate how the Dbl family evolved in all eukaryotic supergroups. By combining probabilistic phylogenetic approaches and functional domain analysis, we show that the human Dbl-like family is made of 71 members, structured into 20 subfamilies. The 71 members were already present in ancestral jawed vertebrates, but several members were subsequently lost in specific clades, up to 12% in birds. The jawed vertebrate repertoire was established from two rounds of duplications that occurred between tunicates, cyclostomes, and jawed vertebrates. Duplicated members showed distinct tissue distributions, conserved at least in Amniotes. All 20 subfamilies have members in Deuterostomes and Protostomes. Nineteen subfamilies are present in Porifera, the first phylum that diverged in Metazoa, 14 in Choanoflagellida and Filasterea, single-celled organisms closely related to Metazoa and three in Fungi, the sister clade to Metazoa. Other eukaryotic supergroups show an extraordinary variability of Dbl-like repertoires as a result of repeated and independent gain and loss events. Last, we observed that in Metazoa, the number of Dbl-like RhoGEFs varies in proportion of cell signaling complexity. Overall, our analysis supports the conclusion that Dbl-like RhoGEFs were present at the origin of eukaryotes and evolved as highly adaptive cell signaling mediators.

Published
2017

34. A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior

Author

Ehrmann, Ingrid, Gazzara, Matthew R., Pagliarini, Vittoria, Dalgliesh, Caroline, Kheirollahi-Chadegani, Mahsa, Yaobo Xu, Cesari, Eleonora, Danilenko, Marina, Maclennan, Marie, Lowdon, Kate, Vogel, Tanja, Keskivali-Bond, Piia, Wells, Sara, Cater, Heather, Fort, Philippe, Santibanez-Koref, Mauro, Middei, Silvia, Sette, Claudio, Clowry, Gavin J., Barash, Yoseph, Cunningham, Mark O., Elliott, David J., Institute of Human Genetics (NEWCASTLE UNIVERSITY), Newcastel University, Department of Biomedicine and Prevention, Università degli Studi di Roma Tor Vergata [Roma], Institute of Anatomy and Cell Biology, Albert-Ludwigs-Universität Freiburg, Mary Lyon Centre, MRC Harwell Institute, Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Medical Research Counc, 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), Dulbecco Telethon Institute/Department of Biology, University of Pennsylvania [Philadelphia], United States Nuclear Regulatory Commission (U.S.NRC), Institute of Genetic Medicine [Newcastle, U.K.], and Newcastle University [Newcastle]

Subjects
Genetics and Molecular Biology (all), hippocampus, Knockout, brain, [SDV.CAN]Life Sciences [q-bio]/Cancer, [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, Biochemistry, Article, Mice, alternative splicing, RNA Precursors, Animals, Homeostasis, Neural Cell Adhesion Molecules, lcsh:QH301-705.5, Adaptor Proteins, Signal Transducing, Settore BIO/16 - ANATOMIA UMANA, Mice, Knockout, Behavior, Behavior, Animal, Animal, Pyramidal Cells, Calcium-Binding Proteins, Signal Transducing, Adaptor Proteins, RNA-Binding Proteins, Neurexin splicing, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, neuron, gene expression, RNA binding proteins, RNA-seq, transcriptome, Alternative Splicing, Synapses, Nerve Net, Biochemistry, Genetics and Molecular Biology (all), [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, lcsh:Biology (General)
Abstract

Summary The brain is made up of trillions of synaptic connections that together form neural networks needed for normal brain function and behavior. SLM2 is a member of a conserved family of RNA binding proteins, including Sam68 and SLM1, that control splicing of Neurexin1-3 pre-mRNAs. Whether SLM2 affects neural network activity is unknown. Here, we find that SLM2 levels are maintained by a homeostatic feedback control pathway that predates the divergence of SLM2 and Sam68. SLM2 also controls the splicing of Tomosyn2, LysoPLD/ATX, Dgkb, Kif21a, and Cask, each of which are important for synapse function. Cortical neural network activity dependent on synaptic connections between SLM2-expressing-pyramidal neurons and interneurons is decreased in Slm2-null mice. Additionally, these mice are anxious and have a decreased ability to recognize novel objects. Our data reveal a pathway of SLM2 homeostatic auto-regulation controlling brain network activity and behavior., Graphical Abstract, Highlights • SLM2 splicing targets are spatially controlled within the hippocampus • RNA-seq reveals SLM2 feedback control and synaptic protein splicing targets • Loss of SLM2 dampens patterns of hippocampal γ oscillations • Loss of SLM2 changes mouse behavior that depends on these neural networks, SLM2 is an RNA binding protein conserved for ∼550 million years. Ehrmann et al. identify a homeostatic feedback pathway that controls SLM2 expression across the brain. Loss of SLM2 protein causes defects in neural network activity and changes mouse behavior.

Published
2016

36. The RPAP3-Cterminal domain identifies R2TP-like quaternary chaperones

Author

Maurizy, Chloe, Quinternet, Marc, Abel, Yoann, Verheggen, Celine, Santo, Paulo E., Bourguet, Maxime, Paiva, Ana C. F., Bragantini, Benoit, Chagot, Marie-Eve, Robert, Marie-Cecile, Abeza, Claire, Fabre, Philippe, Fort, Philippe, Vandermoere, Franck, Sousa, Pedro M. F., Rain, Jean-Christophe, Charpentier, Bruno, Cianferani, Sarah, Bandeiras, Tiago M., Pradet-Balade, Berengere, Manival, Xavier, Bertrand, Edouard, 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), Ingénierie, Biologie et Santé en Lorraine (IBSLor), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Laboratoire de Spectrométrie de Masse BioOrganique (IPHC-DSA), Instituto de Biologia Experimental e Tecnológica (IBET), 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), Hybrigenics [Paris], Hybrigenics, Service de néphrologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre-Institut National de la Santé et de la Recherche Médicale (INSERM), Instituto de Tecnologia Química e Biológica António Xavier (ITQB), Universidade Nova de Lisboa (NOVA), Equipe labellisée Ligue contre le Cancer, Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universidade de Lisboa (ULISBOA), Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] (LSMBO), Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), 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 National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM), Laboratoire de Spectrométrie de Masse BioOrganique, Département des Sciences Analytiques, Institut Pluridisciplinaire Hubert Curien, Strasbourg, France (LSMBO-DSA-IPHC), Centre National de la Recherche Scientifique (CNRS), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), bertrand, edouard, Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Universidade de Lisboa = University of Lisbon (ULISBOA), Centre de recherche en Biologie cellulaire de Montpellier (CRBM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, AAA proteins, [SDV]Life Sciences [q-bio], General Physics and Astronomy, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Chaperone, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Protein Structure, Secondary, Testis, lcsh:Science, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), ComputingMilieux_MISCELLANEOUS, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [SDV] Life Sciences [q-bio], [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Antigens, Surface, Protein Binding, Signal Transduction, Cell biology, RUVBL2, Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hsp90, Chaperone (protein), [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Plasma protein binding, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, GTP-Binding Proteins, Genetics, Humans, GTP-binding protein regulators, HSP90 Heat-Shock Proteins, Protein folding, IP LUMIER, Adaptor Proteins, Signal Transducing, DNA Helicases, Membrane Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, liprin-α2, NMR, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, HEK293 Cells, Membrane protein, ATPases Associated with Diverse Cellular Activities, lcsh:Q, Apoptosis Regulatory Proteins, Carrier Proteins, R2SP, HeLa Cells, Molecular Chaperones
Abstract

R2TP is an HSP90 co-chaperone that assembles important macro-molecular machineries. It is composed of an RPAP3-PIH1D1 heterodimer, which binds the two essential AAA+ATPases RUVBL1/RUVBL2. Here, we resolve the structure of the conserved C-terminal domain of RPAP3, and we show that it directly binds RUVBL1/RUVBL2 hexamers. The human genome encodes two other proteins bearing RPAP3-C-terminal-like domains and three containing PIH-like domains. Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP. This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes. Remarkably, R2SP is required for liprin-α2 expression and for the assembly of liprin-α2 complexes, indicating that R2SP functions in quaternary protein folding. Effects are stronger at 32 °C, suggesting that R2SP could help compensating the lower temperate of testis., R2TP is an HSP90 co-chaperone composed of an RPAP3-PIH1D1 heterodimer, which binds two essential AAA+ ATPases RUVBL1/RUVBL2. Here authors use a structural approach to study RPAP3 and find an RPAP3-like protein (SPAG1) which also forms a co-chaperone complex with PIH1D2 and RUVBL1/2 enriched in testis.

Published
2018

40. SOX9 has distinct regulatory roles in alternative splicing and transcription

Author

Girardot, Michael, Bayet, Elsa, Maurin, Justine, Fort, Philippe, Roux, Pierre, Raynaud, Peggy, 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 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Philippe, Fort, Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Centre de recherche en Biologie cellulaire de Montpellier (CRBM)

Subjects
endocrine system, animal structures, Transcription, Genetic, RNA Splicing, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, [SDV.CAN] Life Sciences [q-bio]/Cancer, stomatognathic system, [SDV.BID.SPT] Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], RNA and RNA-protein complexes, Humans, RNA, Messenger, Cells, Cultured, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, RNA-Binding Proteins, SOX9 Transcription Factor, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, musculoskeletal system, Alternative Splicing, HEK293 Cells, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Gene Expression Regulation, Gene Knockdown Techniques, embryonic structures, Protein Binding
Abstract

International audience; SOX9 is known as a crucial transcription factor for various developmental processes and for tissue homeostasis. We examined here its potential role in alternative splicing by analyzing global splicing changes, using RNA-seq of colon tumor cells. We show that SOX9 knockdown alters the splicing of hundreds of genes without affecting their expression levels, revealing that SOX9 controls distinct splicing and transcriptional programs. SOX9 does not affect splicing patterns through the control of splicing factors expression. We identify mutants that uncouple SOX9 splicing function from its transcriptional activity. We demonstrate that SOX9 binds to RNA and associates with several RNA-binding proteins, including the core exon junction complex component Y14. Half of SOX9 splicing targets are also modulated by Y14 and are no longer regulated by SOX9 upon Y14 depletion. Altogether, our work reveals that SOX9 is a moonlighting protein which modulates either transcription or splicing of distinct sets of targets.

Published
2018

45. Binding site density enables paralog-specific activity of SLM2 and Sam68 proteins in Neurexin2 AS4 splicing control

Author

Danilenko, Marina, Dalgliesh, Caroline, Pagliarini, Vittoria, Naro, Chiara, Ehrmann, Ingrid, Feracci, Mikael, Kheirollahi-Chadegani, Mahsa, Tyson-Capper, Alison, Clowry, Gavin J., Fort, Philippe, Dominguez, Cyril, Sette, Claudio, Elliott, David J., Pagliarini, Vittoria (ORCID:0000-0002-2388-0675), Naro, Chiara (ORCID:0000-0002-3135-3218), Sette, Claudio (ORCID:0000-0003-2864-8266), Danilenko, Marina, Dalgliesh, Caroline, Pagliarini, Vittoria, Naro, Chiara, Ehrmann, Ingrid, Feracci, Mikael, Kheirollahi-Chadegani, Mahsa, Tyson-Capper, Alison, Clowry, Gavin J., Fort, Philippe, Dominguez, Cyril, Sette, Claudio, Elliott, David J., Pagliarini, Vittoria (ORCID:0000-0002-2388-0675), Naro, Chiara (ORCID:0000-0002-3135-3218), and Sette, Claudio (ORCID:0000-0003-2864-8266)

Abstract

SLM2 and Sam68 are splicing regulator paralogs that usually overlap in function, yet only SLM2 and not Sam68 controls the Neurexin2 AS4 exon important for brain function. Herein we find that SLM2 and Sam68 similarly bind to Neurexin2 pre-mRNA, both within the mouse cortex and in vitro. Protein domain-swap experiments identify a region including the STAR domain that differentiates SLM2 and Sam68 activity in splicing target selection, and confirm that this is not established via the variant amino acids involved in RNA contact. However, far fewer SLM2 and Sam68 RNA binding sites flank the Neurexin2 AS4 exon, compared with those flanking the Neurexin1 and Neurexin3 AS4 exons under joint control by both Sam68 and SLM2. Doubling binding site numbers switched paralog sensitivity, by placing the Neurexin2 AS4 exon under joint splicing control by both Sam68 and SLM2. Our data support a model where the density of shared RNA binding sites around a target exon, rather than different paralog-specific protein-RNA binding sites, controls functional target specificity between SLM2 and Sam68 on the Neurexin2 AS4 exon. Similar models might explain differential control by other splicing regulators within families of paralogs with indistinguishable RNA binding sites.

Published
2017

47. PIP30/FAM192A is a novel regulator of the nuclear proteasome activator PA28γ

Author

Jonik-Nowak, Beata, primary, Menneteau, Thomas, additional, Fesquet, Didier, additional, Baldin, Véronique, additional, Bonne-Andrea, Catherine, additional, Méchali, Francisca, additional, Fabre, Bertrand, additional, Boisguerin, Prisca, additional, de Rossi, Sylvain, additional, Henriquet, Corinne, additional, Pugnière, Martine, additional, Ducoux-Petit, Manuelle, additional, Burlet-Schiltz, Odile, additional, Lamond, Angus I., additional, Fort, Philippe, additional, Boulon, Séverine, additional, Bousquet, Marie-Pierre, additional, and Coux, Olivier, additional

Published
2017
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48. Binding site density enables paralog-specific activity of SLM2 and Sam68 proteins in Neurexin2 AS4 splicing control

Author

Danilenko, Marina, primary, Dalgliesh, Caroline, additional, Pagliarini, Vittoria, additional, Naro, Chiara, additional, Ehrmann, Ingrid, additional, Feracci, Mikael, additional, Kheirollahi-Chadegani, Mahsa, additional, Tyson-Capper, Alison, additional, Clowry, Gavin J, additional, Fort, Philippe, additional, Dominguez, Cyril, additional, Sette, Claudio, additional, and Elliott, David J., additional

Published
2016
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49. Evolution of Proteasome Regulators in Eukaryotes

Author

Fort, Philippe, Kajava, Andrey, Delsuc, Frédéric, Coux, Olivier, 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), National Research University of Information Technologies, Mechanics and Optics [St. Petersburg] (ITMO), 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), Centre de recherche en Biologie cellulaire de Montpellier (CRBM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE)

Subjects
[SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, proteasome, evolution, PA28, PI31, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, PA200, PA700
Abstract

International audience; All living organisms require protein degradation to terminate biological processes and remove damaged proteins. One such machine is the 20S proteasome, a specialized barrel-shaped and compartmentalized multicatalytic protease. The activity of the 20S protea-some generally requires the binding of regulators/proteasome activators (PAs), which control the entrance of substrates. These include the PA700 (19S complex), which assembles with the 20S and forms the 26S proteasome and allows the efficient degradation of proteins usually labeled by ubiquitin tags, PA200 and PA28, which are involved in proteolysis through ubiquitin-independent mechanisms and PI31, which was initially identified as a 20S inhibitor in vitro. Unlike 20S proteasome, shown to be present in all Eukaryotes and Archaea, the evolutionary history of PAs remained fragmentary. Here, we made a comprehensive survey and phylogenetic analyses of the four types of regulators in 17 clades covering most of the eukaryotic supergroups. We found remarkable conservation of each PA700 subunit in all eukaryotes, indicating that the current complex PA700 structure was already set up in the last eukaryotic common ancestor (LECA). Also present in LECA, PA200, PA28, and PI31 showed a more contrasted evolutionary picture, because many lineages have subsequently lost one or two of them. The paramount conservation of PA700 composition in all eukaryotes and the dynamic evolution of PA200, PA28, and PI31 are discussed in the light of current knowledge on their physiological roles.

Published
2015

50. Neural differentiation modulates the vertebrate brain specific splicing program

Author

Madgwick, Alicia, Fort, Philippe, Hanson, Peter S., Thibault, Philippe, Gaudreau, Marie-Claude, Lutfalla, Georges, Möröy, Tarik, Abou Elela, Sherif, Chaudhry, Bill, Elliott, David J., Morris, Christopher M., Venables, Julian P., 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), Newcastle University [Newcastle], Université de Sherbrooke (UdeS), Institut de Recherches Cliniques de Montréal (IRCM), Université de Montréal (UdeM), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institute of Genetic Medicine [Newcastle, U.K.], and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1)

Subjects
Neurons, animal structures, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, lcsh:R, lcsh:Medicine, Cell Differentiation, Real-Time Polymerase Chain Reaction, Alternative Splicing, Mice, Vertebrates, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, lcsh:Q, lcsh:Science, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Zebrafish, Research Article
Abstract

International audience; Alternative splicing patterns are known to vary between tissues but these patterns have been found to be predominantly peculiar to one species or another, implying only a limited function in fundamental neural biology. Here we used high-throughput RT-PCR to monitor the expression pattern of all the annotated simple alternative splicing events (ASEs) in the Reference Sequence Database, in different mouse tissues and identified 93 brain-specific events that shift from one isoform to another (switch-like) between brain and other tissues. Consistent with an important function, regulation of a core set of 9 conserved switch-like ASEs is highly conserved, as they have the same pattern of tissue-specific splicing in all vertebrates tested: human, mouse and zebrafish. Several of these ASEs are embedded within genes that encode proteins associated with the neuronal microtubule network, and show a dramatic and concerted shift within a short time window of human neural stem cell differentiation. Similarly these exons are dynamically regulated in zebrafish development. These data demonstrate that although alternative splicing patterns often vary between species , there is nonetheless a core set of vertebrate brain-specific ASEs that are conserved between species and associated with neural differentiation.

Published
2015

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