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1. FUS-mediated regulation of acetylcholine receptor transcription at neuromuscular junctions is compromised in amyotrophic lateral sclerosis

Author

Chantal Sellier, Nick H.M. van Bakel, Amila Zuko, Céline Sijlmans, Sina Mersmann, Anne-Laurence Boutillier, Annemarie Hübers, Amr Aly, Marina Wagner, Stéphane Dieterlé, Moushami Mallik, Marc-Antoine Goy, Clotilde Lagier-Tourenne, Gina Picchiarelli, Albert C. Ludolph, Luc Dupuis, Erik Storkebaum, Julia Higelin, Angela Rosenbohm, Li Zhang, Tobias M. Boeckers, Marije Been, Maria Demestre, Jelena Scekic-Zahirovic, Nadia Messaddeq, Inmaculada Sanjuan-Ruiz, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Laboratoire de signalisation moléculaire et neurodégénerescence, Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie, Universität Ulm - Ulm University [Ulm, Allemagne], Institut for Anatomy and Cell Biology, Laboratoire de neurosciences cognitives et adaptatives (LNCA), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, Muscle Fibers, Skeletal, metabolism [Neuromuscular Junction], Mice, 0302 clinical medicine, Postsynaptic potential, Receptors, Cholinergic, Gene Knock-In Techniques, Amyotrophic lateral sclerosis, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Molecular Neurobiology, metabolism [RNA-Binding Protein FUS], Mice, Knockout, Motor Neurons, physiology [RNA-Binding Protein FUS], Myogenesis, General Neuroscience, ETS transcription factor family, FUS protein, mouse, physiopathology [Amyotrophic Lateral Sclerosis], medicine.anatomical_structure, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Adult, pathology [Motor Neurons], physiology [Gene Expression Regulation], Neuromuscular Junction, Biology, pathology [Neuromuscular Junction], Neuromuscular junction, Article, 03 medical and health sciences, Young Adult, ddc:570, metabolism [Receptors, Cholinergic], medicine, Animals, Humans, pathology [Amyotrophic Lateral Sclerosis], Acetylcholine receptor, [SCCO.NEUR]Cognitive science/Neuroscience, Amyotrophic Lateral Sclerosis, Skeletal muscle, Motor neuron, physiopathology [Nerve Degeneration], medicine.disease, 030104 developmental biology, Gene Expression Regulation, Nerve Degeneration, RNA-Binding Protein FUS, pathology [Muscle Fibers, Skeletal], genetics [RNA-Binding Protein FUS], Neuroscience, 030217 neurology & neurosurgery
Abstract

Neuromuscular junction (NMJ) disruption is an early pathogenic event in amyotrophic lateral sclerosis (ALS). Yet, direct links between NMJ pathways and ALS-associated genes such as FUS, whose heterozygous mutations cause aggressive forms of ALS, remain elusive. In a knock-in Fus-ALS mouse model, we identified postsynaptic NMJ defects in newborn homozygous mutants that were attributable to mutant FUS toxicity in skeletal muscle. Adult heterozygous knock-in mice displayed smaller neuromuscular endplates that denervated before motor neuron loss, which is consistent with 'dying-back' neuronopathy. FUS was enriched in subsynaptic myonuclei, and this innervation-dependent enrichment was distorted in FUS-ALS. Mechanistically, FUS collaborates with the ETS transcription factor ERM to stimulate transcription of acetylcholine receptor genes. Co-cultures of induced pluripotent stem cell-derived motor neurons and myotubes from patients with FUS-ALS revealed endplate maturation defects due to intrinsic FUS toxicity in both motor neurons and myotubes. Thus, FUS regulates acetylcholine receptor gene expression in subsynaptic myonuclei, and muscle-intrinsic toxicity of ALS mutant FUS may contribute to dying-back motor neuronopathy.

Published
2019
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2. Shank2 Mutant Mice Display Hyperactivity Insensitive to Methylphenidate and Reduced Flexibility in Social Motivation, but Normal Social Recognition

Author

Fabrice de Chaumont, Tobias M. Boeckers, Nicolas Torquet, Thomas Bourgeron, Anne-Marie Le Sourd, Julie Lévi-Strauss, Elodie Ey, Allain-Thibeault Ferhat, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Analyse d'images biologiques - Biological Image Analysis (BIA), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut for Anatomy and Cell Biology, Universität Ulm - Ulm University [Ulm, Allemagne], Génétique Humaine et Fonctions Cognitives, Université Paris Diderot - Paris 7 (UPD7), This work was partially funded by the Institut Pasteur, the Bettencourt-Schueller Foundation, the Fondation de France, the Orange Foundation, the Centre National de la Recherche Scientifique, the University Paris Diderot, and the BioPsy LabEX. The research leading to these results has also received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, resources of which are composed of financial contribution from the European Union’s Seventh Framework Program (FP7/2007-2013) and EFPIA companies’ in kind contribution., We thank the reviewers for helpful comments that improved the manuscript., Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Analyse d'Images quantitatives (AIQ)

Subjects
0301 basic medicine, Scaffold protein, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Mutant, autism, methylphenidate, Biology, social motivation, lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, Exon, 0302 clinical medicine, medicine, mouse models, Social isolation, social recognition, Molecular Biology, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Original Research, Methylphenidate, [SCCO.NEUR]Cognitive science/Neuroscience, Social environment, medicine.disease, SHANK2, hyperactivity, ultrasonic vocalization, 030104 developmental biology, Shank2, Autism, medicine.symptom, Neuroscience, 030217 neurology & neurosurgery, medicine.drug
Abstract

International audience; Mouse models of autism can be used to study evolutionarily conserved mechanisms underlying behavioral abnormalities in social communication and repetitive behaviors. SHANK genes code for synaptic scaffolding proteins at excitatory synapses and mutations in all SHANK genes have been associated with autism. Here, we present three behavioral aspects of the mutant mice deleted for exon 16 in Shank2. First, we treated Shank2 mutant mice with methylphenidate to rescue the hyperactivity. Our failure to do so suggests that the hyperactivity displayed by Shank2 mutant mice is not related to the one displayed by the typical mouse models of hyperactivity, and might be more closely related to manic-like behaviors. Second, by testing the effect of group housing and social isolation on social interest, we highlighted that Shank2 mutant mice lack the typical flexibility to modulate social interest, in comparison with wild-type littermates. Finally, we established a new protocol to test for social recognition in a social context. We used this protocol to show that Shank2 mutant mice were able to discriminate familiar and unknown conspecifics in free interactions. Altogether, these studies shed some light on specific aspects of the behavioral defects displayed by the Shank2 mouse model. Such information could be used to orient therapeutic strategies and to design more specific tests to characterize the complex behavior of mouse models of autism.

Published
2018
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3. The Autism ProSAP1/Shank2 mouse model displays quantitative and structural abnormalities in ultrasonic vocalisations

Author

Thomas Bourgeron, Philippe Faure, Tobias M. Boeckers, Elodie Ey, Nicolas Torquet, Anne-Marie Le Sourd, Claire S. Leblond, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut for Anatomy and Cell Biology, Universität Ulm - Ulm University [Ulm, Allemagne], Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Fondation de France, bythe ANR FLEXNEURIM [ANR09BLAN034003], by the ANR [ANR-08-MNPS-037-01–SynGen], by Neuron-ERANET (EUHF-AUTISM), by the Fondation Orange, by the Fondation FondaMentale, by the Fondation Bettencourt–Schueller. The research leading to these results has also received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution, ANR-09-BLAN-0340,FLEXNEURIM,Neurobiologie intégrative des comportements flexibles dans des modèles animaux par imagerie computationnelle : application en conditions normales et pathologiques(2009), ANR-08-MNPS-0037,SynGen-ASD-LD,Genes synaptiques de l'autisme et du retard mental(2008), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, medicine.medical_specialty, Vocal communication, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Autistic Disorder, MESH: Vocalization, Animal, Nerve Tissue Proteins, Audiology, Biology, Mouse model, 03 medical and health sciences, Mice, Behavioral Neuroscience, 0302 clinical medicine, ProSAP1/Shank2, medicine, Animals, In patient, MESH: Animals, MESH: Nerve Tissue Proteins, Autistic Disorder, Autism spectrum disorder, MESH: Mice, 030304 developmental biology, 0303 health sciences, Communication, business.industry, Ultrasonic vocalization, Communication defects, medicine.disease, MESH: Male, SHANK2, Synaptic protein, Disease Models, Animal, Autism, Ultrasonic sensor, Vocalization, Animal, MESH: Disease Models, Animal, business, 030217 neurology & neurosurgery, Peak frequency
Abstract

International audience; Mouse ultrasonic vocalisations have been often used as a paradigm to extrapolate vocal communication defects observed in patients with autism spectrum disorders (ASD). The role of these vocalisations as well as their development, structure and informational content, however, remain largely unknown. In the present study, we characterised in depth the emission of pup and adult ultrasonic vocalisations of wild-type mice and their ProSAP1/Shank2(-/-) littermates lacking a synaptic scaffold protein mutated in ASD. We hypothesised that the vocal behaviour of ProSAP1/Shank2(-/-) mice not only differs from the vocal behaviour of their wild-type littermates in a quantitative way, but also presents more qualitative abnormalities in temporal organisation and acoustic structure. We first quantified the rate of emission of ultrasonic vocalisations, and analysed the organisation of vocalisations sequences using Markov models. We subsequently measured duration and peak frequency characteristics of each ultrasonic vocalisation, to characterise their acoustic structure. In wild-type mice, we found a high level of organisation in sequences of ultrasonic vocalisations, suggesting a communicative function in this complex system. Very limited significant sex-related variations were detected in their usage and acoustic structure, even in adult mice. In adult ProSAP1/Shank2(-/-) mice, we found abnormalities in the call usage and the structure of ultrasonic vocalisations. Both ProSAP1/Shank2(-/-) male and female mice uttered less vocalisations with a different call distribution and at lower peak frequency in comparison with wild-type littermates. This study provides a comprehensive framework to characterise abnormalities of ultrasonic vocalisations in mice and confirms that ProSAP1/Shank2(-/-) mice represent a relevant model to study communication defects.

Published
2013
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4. Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments

Author

Anne Claude Tabet, Françoise Devillard, Christelle M. Durand, Dominique Bonneau, Caroline Schluth-Bolard, Hugo Peyre, Frédérique Amsellem, Jennifer L. Howe, Brigitte Assouline, Laurence Perrin, Patrick Edery, Gudrun A. Rappold, Alexis Brice, Tobias M. Boeckers, Kevin Mouzat, Mary Coleman, Diana Zelenika, Guy A. Rouleau, Christel Depienne, Alexandra Afenjar, Pilar Galan, Peter Szatmari, Coline Stordeur, Fabienne Giuliano, Thomas Bourgeron, Delphine Héron, Anthony P. Monaco, Aurélia Jacquette, Marion Leboyer, Elena Maestrini, Roberto Toro, Anne Polge, Serge Lumbroso, Richard Delorme, Maria Råstam, François Rivier, Richard Holt, Stephen W. Scherer, Jessica Guibert, Elodie Ey, Dalila Pinto, Christopher Gillberg, Béatrice Regnault, Fanny Laffargue, Claire S. Leblond, Julie Gauthier, Nathalie Lemière, James Lespinasse, Alexandre Mathieu, Michael J. Schmeisser, Jean Chiesa, Agnès Rastetter, Marc Delepine, Catalina Betancur, I. Carina Gillberg, Daisuke Sato, Mark Lathrop, Caroline Nava, Damien Sanlaville, Guillaume Huguet, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Biochimie, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Laboratoire de diagnotic moléculaire, CHU Sainte Justine [Montréal], Service de génétique médicale, Hôpital l'Archet, Service de Psychiatrie de l'Enfant et de l'Adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Departments of Psychiatry, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Seaver Autism Center-, The Mindich Child Health & Development Institute, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Laboratoire de sciences cognitives et psycholinguistique (LSCP), Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS), Fondation FondaMental [Créteil], Department of Clinical Sciences, Lund University [Lund], Gillberg Neuropsychiatry Centre [Göteborg, Sueden], Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU), Department of Molecular Human Genetics, Universität Heidelberg [Heidelberg] = Heidelberg University, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant, Unité Pédopsychiatrique et Neuropédiatrique de Diagnostic et d'Evaluation des Troubles Envahissants du Développement, Centre Alpin de DIagnostic Précoce de l'Autisme - CADIPA-Centre Hospitalier Alpes Isère, Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Département de Génétique Chromosomique, Bâtiment Hôtel Dieu - Centre Hospitalier de Chambéry, Laboratoire de Cytogénétique, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Biochimie et Génétique, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Génotypage des Eucaryotes (Plate-Forme), Institut Pasteur [Paris] (IP), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut for Anatomy and Cell Biology, Universität Ulm - Ulm University [Ulm, Allemagne], Foundation for Autism Research, Center of Excellence in Neuroscience, CHU de Montréal, Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Institute of Child Health, University College of London [London] (UCL), This work was funded by the Institut Pasteur, CNRS, INSERM, AP-HP, University Paris Diderot, the Bettencourt-Schueller foundation, the Orange foundation, the FondaMental foundation, the Conny-Maeva foundation, the Cognacq-Jay foundation, the ANR (ANR-08-MNPS-037-01 - SynGen), Neuron- ERANET (EUHF-AUTISM), the DFG (BO1718/3-1, 4-1) and Baustein L.SBN.0081., Leblond CS, Nava C, Polge A, Gauthier J, Huguet G, Lumbroso S, Giuliano F, Stordeur C, Depienne C, Mouzat K, Pinto D, Howe J, Lemière N, Durand CM, Guibert J, Ey E, Toro R, Peyre H, Mathieu A, Amsellem F, Rastam M, Gillberg IC, Rappold GA, Holt R, Monaco AP, Maestrini E, Galan P, Heron D, Jacquette A, Afenjar A, Rastetter A, Brice A, Devillard F, Assouline B, Laffargue F, Lespinasse J, Chiesa J, Rivier F, Bonneau D, Regnault B, Zelenika D, Delepine M, Lathrop M, Sanlaville D, Schluth-Bolard C, Edery P, Perrin L, Tabet AC, Schmeisser MJ, Boeckers TM, Coleman M, Sato D, Szatmari P, Scherer SW, Rouleau GA, Betancur C, Leboyer M, Gillberg C, Delorme R, Bourgeron T, Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Universität Heidelberg [Heidelberg], University of Oxford [Oxford], Unité Fonctionnelle de Génétique Clinique [CHU Pitié Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pasteur [Paris], Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon (CRNL), and Betancur, Catalina

Subjects
Male, Cancer Research, [SDV.GEN] Life Sciences [q-bio]/Genetics, medicine.disease_cause, GENE DELETION, 0302 clinical medicine, Cognition, Intellectual disability, Child, Genetics (clinical), Genetics, Psychiatry, Neurons, 0303 health sciences, Mutation, SDV:GEN, META-ANALYSIS, Penetrance, Hypotonia, 3. Good health, SHANK2, Autism spectrum disorder, Female, medicine.symptom, Research Article, lcsh:QH426-470, DNA Copy Number Variations, Nerve Tissue Proteins, Biology, 03 medical and health sciences, Intellectual Disability, mental disorders, medicine, Humans, Clinical significance, AUTISM, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Biology and Life Sciences, Human Genetics, medicine.disease, lcsh:Genetics, Child Development Disorders, Pervasive, Case-Control Studies, Synapses, Autism, Cognition Disorders, 030217 neurology & neurosurgery
Abstract

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability—more than 1 in 50—warrant its consideration for mutation screening in clinical practice., Author Summary Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders. Mutations altering genes involved in the junction between brain cells have been repeatedly associated in ASD. For example, SHANK1, SHANK2 and SHANK3 emerged as one family of genes that are associated with ASD. However, little was known about the number of patients carrying these mutations and the clinical outcome. Here, we performed a new genetic screen of SHANK mutations and these results were analyzed in combination with those of the literature. In summary, SHANK mutations account for ∼1% of patients with ASD and were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. Given the high frequency and impact of SHANK3 mutations in individuals with ASD and intellectual disability—more than 1 in 50—this gene should be screened for mutations in clinical practice.

Published
2014
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5. A sparse approach to build shape models with routine clinical data

Author

Bernhard Meyer, Ehab Shiban, Benjamin Gutierrez, Nassir Navab, Diana Mateus, Jens Lehmberg, Computer Aided Medical Procedures & Augmented Reality (CAMPAR), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz-Zentrum München (HZM), Institut for Anatomy and Cell Biology, and Universität Ulm - Ulm University [Ulm, Allemagne]

Subjects
Computer science, business.industry, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], 02 engineering and technology, Machine learning, computer.software_genre, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, 0202 electrical engineering, electronic engineering, information engineering, [INFO]Computer Science [cs], 020201 artificial intelligence & image processing, Artificial intelligence, business, computer, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2014
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6. Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2

Author

Juergen Bockmann, Thomas Bourgeron, A. Vanessa Stempel, Ehab Shiban, Michael R. Kreutz, Dirk Montag, Karl-Heinz Smalla, Roberto Toro, Tobias M. Boeckers, Andreas M. Grabrucker, Elodie Ey, Angelika Kuebler, Nicolas Torquet, Christina Spilker, Claire S. Leblond, Anne-Marie Le Sourd, Philippe Faure, Boris V. Skryabin, Detlef Balschun, Dietmar Schmitz, Anna-Lena Janssen, Susanne tom Dieck, Stephanie Wegener, Patrick T Udvardi, Sarah A. Shoichet, Eckart D. Gundelfinger, Michael J. Schmeisser, Institut for Anatomy and Cell Biology, Universität Ulm - Ulm University [Ulm, Allemagne], Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Leibniz Institute for Neurobiology, research institution for learning and memory, Laboratory of Biological Psychology, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of Münster, Max Planck Institute for Brain Research, Max-Planck-Gesellschaft, Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), M.J.S. is further supported by Baustein 3.2 (L.SBN.0081), E.E. by the Fondation de France and the Agence Nationale de la Recherche (ANR) FLEXNEURIM (ANR09BLAN034003), S.W. and A.V.S. by the Deutsche Forschungsgemeinschaft (DFG) (GRK 1123), A.M.G. by Baustein 3.2 (L.SBN.0083), S.A.S by the DFG (EXC 257), D.S. by the DFG (SFB 618, SFB 665, EXC 257), theBundesministerium für Bildung und Forschung (BMBF) (BCCN, BFNL) and the Einstein Foundation, M.R.K.by the DFG(SFB779),C.S.L.,R.T.,N.T., A.LS. and T.B.by the ANR (ANR-08-MNPS-037-01 - SynGen), Neuron-ERANET (EUHF-AUTISM), Fondation Orange and the Fondation FondaMentale, P.F.by the Bettencourt-Schueller Fondation, R.T.,T.B.,P.F.by the CNRS Neuroinformatic, E.D.G. by the DFG(SFB779) and the BMBF (EraNET Neuron), and T.M.B. by the DFG (Bo 1718/3-1 and 1718/4-1, SFB 497/B8)., ANR-09-BLAN-0340,FLEXNEURIM,Neurobiologie intégrative des comportements flexibles dans des modèles animaux par imagerie computationnelle : application en conditions normales et pathologiques(2009), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Westfälische Wilhelms-Universität Münster = University of Münster (WWU)

Subjects
Male, Dendritic spine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Synapses, Synapse, Mice, 0302 clinical medicine, MESH: Behavior, Animal, MESH: Up-Regulation, MESH: Animals, MESH: Nerve Tissue Proteins, Psychomotor Agitation, 0303 health sciences, Multidisciplinary, MESH: Receptors, Ionotropic Glutamate, Behavior, Animal, Glutamate receptor, MESH: Psychomotor Agitation, SHANK2, Up-Regulation, Excitatory postsynaptic potential, Female, Dendritic Spines, MESH: Vocalization, Animal, MESH: Autistic Disorder, Nerve Tissue Proteins, Neurotransmission, Biology, Receptors, Ionotropic Glutamate, MESH: Dendritic Spines, 03 medical and health sciences, MESH: Mice, Inbred C57BL, medicine, Animals, Autistic Disorder, MESH: Mice, 030304 developmental biology, Adaptor Proteins, Signal Transducing, MESH: Adaptor Proteins, Signal Transducing, medicine.disease, MESH: Male, Mice, Inbred C57BL, Immunology, Synapses, Autism, Vocalization, Animal, Postsynaptic density, Neuroscience, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour. Mutations in synaptic proteins such as neuroligins, neurexins, GKAPs/SAPAPs and ProSAPs/Shanks were identified in patients with autism spectrum disorder, but the causative mechanisms remain largely unknown. ProSAPs/Shanks build large homo- and heteromeric protein complexes at excitatory synapses and organize the complex protein machinery of the postsynaptic density in a laminar fashion. Here we demonstrate that genetic deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3. Moreover, ProSAP1/Shank2(-/-) mutants exhibit fewer dendritic spines and show reduced basal synaptic transmission, a reduced frequency of miniature excitatory postsynaptic currents and enhanced N-methyl-d-aspartate receptor-mediated excitatory currents at the physiological level. Mutants are extremely hyperactive and display profound autistic-like behavioural alterations including repetitive grooming as well as abnormalities in vocal and social behaviours. By comparing the data on ProSAP1/Shank2(-/-) mutants with ProSAP2/Shank3αβ(-/-) mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype.

Published
2012
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7. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer.

Author

Sagiv JY, Michaeli J, Assi S, Mishalian I, Kisos H, Levy L, Damti P, Lumbroso D, Polyansky L, Sionov RV, Ariel A, Hovav AH, Henke E, Fridlender ZG, and Granot Z

Subjects
Animals, Cell Line, Cells, Cultured, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms immunology, Neoplasms pathology, Neutrophils cytology
Abstract

Controversy surrounds neutrophil function in cancer because neutrophils were shown to provide both pro- and antitumor functions. We identified a heterogeneous subset of low-density neutrophils (LDNs) that appear transiently in self-resolving inflammation but accumulate continuously with cancer progression. LDNs display impaired neutrophil function and immunosuppressive properties, characteristics that are in stark contrast to those of mature, high-density neutrophils (HDNs). LDNs consist of both immature myeloid-derived suppressor cells (MDSCs) and mature cells that are derived from HDNs in a TGF-β-dependent mechanism. Our findings identify three distinct populations of circulating neutrophils and challenge the concept that mature neutrophils have limited plasticity. Furthermore, our findings provide a mechanistic explanation to mitigate the controversy surrounding neutrophil function in cancer., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2015
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