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1. Tubulin post‐translational modifications control neuronal development and functions

Author

Moutin, Marie‐Jo, Bosc, Christophe, Peris, Leticia, Andrieux, Annie, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), and Moutin, Marie-Jo

Subjects
neuro‐diseases, neuro-diseases, Acetylation, Review Article, macromolecular substances, tyrosination, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Microtubules, neuron, tubulin, post-translational modifications, post‐translational modifications, Review Articles, Protein Processing, Post-Translational, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cytoskeleton
Abstract

International audience; Microtubules (MTs) are an essential component of the neuronal cytoskeleton; they are involved in various aspects of neuron development, maintenance, and functions including polarization, synaptic plasticity, and transport. Neuronal MTs are highly heterogeneous due to the presence of multiple tubulin isotypes and extensive post-translational modifications (PTMs). These PTMs—most notably detyrosination, acetylation, and polyglutamylation—have emerged as important regulators of the neuronal microtubule cytoskeleton. With this review, we summarize what is currently known about the impact of tubulin PTMs on microtubule dynamics, neuronal differentiation, plasticity, and transport as well as on brain function in normal and pathological conditions, in particular during neuro-degeneration. The main therapeutic approaches to neuro-diseases based on the modulation of tubulin PTMs are also summarized. Overall, the review indicates how tubulin PTMs can generate a large number of functionally specialized microtubule sub-networks, each of which is crucial to specific neuronal features.

Published
2020
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2. A high variability of arterial Doppler waveform descriptions exists in China

Author

Bouet, Valentine, Percelay, Solenn, Leroux, Elise, Diarra, Boubacar, Leger, Marianne, Delcroix, Nicolas, Andrieux, Annie, Dollfus, Sonia, Freret, Thomas, Boulouard, Michel, Peking University [Beijing], Austin Hospital [Melbourne], Austin Health, Jobst Vascular Institute [Promedica Toledo Hospital], Mobilités : Vieillissement, Pathologie, Santé (COMETE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], 7172209, Natural Science Foundation of Beijing Municipality, Université de Caen Normandie - UFR Santé (UNICAEN Santé), Normandie Université (NU)-Normandie Université (NU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), GIP Cyceron (Cyceron), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Service de psychiatrie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), and Jonchère, Laurent

Subjects
China, medicine.medical_specialty, Doppler classification, duplex ultrasound, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, peripheral artery disease, 030218 nuclear medicine & medical imaging, Peripheral Arterial Disease, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Internal medicine, Doppler waveform, Humans, Medicine, Peripheral artery disease (PAD), ComputingMilieux_MISCELLANEOUS, vascular imaging/diagnostics, Observer Variation, business.industry, Reproducibility of Results, Ultrasonography, Doppler, Arteries, medicine.disease, [SDV] Life Sciences [q-bio], Cardiology, Doppler waveforms, Cardiology and Cardiovascular Medicine, business
Abstract

International audience

Published
2020
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3. A neurodevelopmental TUBB2B β-tubulin mutation impairs Bim1 (yeast EB1)-dependent spindle positioning

Author

Denarier, Eric, Brousse, Carine, Sissoko, Abdoulaye, Andrieux, Annie, Boscheron, Cécile, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Physiopathologie du Cytosquelette (GPC), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Transfusion Sanguine [Paris] (INTS), Université Paris Descartes - Paris 5 (UPD5), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Thomas, Frank

Subjects
TUBB2B, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], QH301-705.5, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Science, Microtubule, macromolecular substances, Biology (General), Yeast, Spindle positioning, Research Article, EB1
Abstract

Malformations of the human cerebral cortex can be caused by mutations in tubulins that associate to compose microtubules. Cerebral cortical folding relies on neuronal migration and on progenitor proliferation partly dictated by microtubule-dependent mitotic spindle positioning. A single amino acid change, F265L, in the conserved TUBB2B β-tubulin gene has been identified in patients with abnormal cortex formation. A caveat for studying this mutation in mammalian cells is that nine genes encode β-tubulin in human. Here, we generate a yeast strain expressing F265L tubulin mutant as the sole source of β-tubulin. The F265L mutation does not preclude expression of a stable β-tubulin protein which is incorporated into microtubules. However, impaired cell growth was observed at high temperatures along with altered microtubule dynamics and stability. In addition, F265L mutation produces a highly specific mitotic spindle positioning defect related to Bim1 (yeast EB1) dysfunction. Indeed, F265L cells display an abnormal Bim1 recruitment profile at microtubule plus-ends. These results indicate that the F265L β-tubulin mutation affects microtubule plus-end complexes known to be important for microtubule dynamics and for microtubule function during mitotic spindle positioning., Summary: Patients with intellectual disabilities carry a F265L mutation in TUBB2B β-tubulin gene. Yeast used as a cellular model reveals spindle mis-positioning associated with reduced yeast EB1 affinity for microtubule plus-ends.

Published
2019
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4. Schizophrenia: validity of a 3-hit mouse model

Author

Percelay, Solenn, Freret, Thomas, Diarra, Boubacar, Delcroix, Nicolas, Leroux, Elise, Andrieux, Annie, Dollfus, Sonia, Boulouard, Michel, BouËt, Valentine, Mobilités : Vieillissement, Pathologie, Santé (COMETE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Reference Health Center of the district of Ouelessebougou [Ouelessebougou, Mali], Centre-Imagerie, Neurosciences, et Application aux Pathologies (CI-NAPS - UMR 6232), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagerie et Stratégies Thérapeutiques de la Schizophrénie (ISTS), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), INSERM U836, équipe 1, Physiopathologie du cytosquelette, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Federation of European Neuroscience Societies, Percelay, Solenn, Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuro-imagerie fonctionnelle et métabolique (ANTE-INSERM U836, équipe 5), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SCCO]Cognitive science, model, mice, parvalbumin-positive neurons, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Schizophrenia, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, imaging, [SCCO] Cognitive science, behaviour
Abstract

International audience; Schizophrenia is a frequent psychiatric disease (prevalence 1%). Unfortunately, current treatments are unsatisfactory: they do not cover the entirety of symptoms, they can even worsen them, and they are inefficient in 30% of patients. There is a crucial need for new drugs, which requires more relevant animal models taking into account the multifactorial nature of this pathology. We built a new animal model gathering three factors: a genetic predisposition (partial deletion of the MAP6 (Microtubule-Associated Protein 6) with an early post-natal stress (maternal separation at the age of 9 days during 24h) and a late disturbance during adolescence (THC from post-natal day 32 to 52; 8 mg/kg). A particular focus was made on behavior, brain imaging, and immunohistochemistry. The 3-hit combination induces specific decrease in spontaneous activity in the open-field, in sociability in the approach-avoidance test, and in working memory performances. In vivo and post-mortem MRI revealed a decrease in cortical thickness and in hippocampus volume, and a loss of integrity of callosal fibers (less axons, less myelin). Moreover, a decrease in density of parvalbumin-positive neurons was observed in CA1 of hippocampus. To conclude, 3-hit combination causes several symptoms mimicking negative and cognitive symptoms of schizophrenia, accompanied with structural changes bringing a high face validity. Moreover, it possesses a strong construct validity which fits with gene x environment interactions hypothesis of schizophrenia. The predictive validity is currently investigated by using lurasidone. The model is expected to be a powerful tool to test new therapeutic strategies for the treatment of schizophrenia.

Published
2018

5. Cell-Intrinsic Control of Interneuron Migration Drives Cortical Morphogenesis

Author

Silva, Carla G., Peyre, Elise, Adhikari, Mohit, Tielens, Sylvia, Tanco, Sebastian, Van Damme, Petra, Magno, Lorenzo, Crusy, Nathalie, Agirman, Gulistan, Magiera, Maria M., Kessaris, Nicoletta, Malgrange, Brigitte, Andrieux, Annie, Janke, Carsten, Nguyen, Laurent, GIGA-Neurosciences [Université Liège], GIGA [Université Liège], Université de Liège-Université de Liège, Universitat Pompeu Fabra [Barcelona] (UPF), Universiteit Gent = Ghent University [Belgium] (UGENT), University College of London [London] (UCL), Institut Curie [Paris], Stress génotoxiques et cancer, Université Paris-Sud - Paris 11 (UP11)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Organisation Fonctionnelle du Cytosquelette, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR27, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universiteit Gent = Ghent University (UGENT), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and ANR-17-CE13-0021,TUBTUNE,Le ' code tubuline ' : un mécanisme qui adapte les fonctions des microtubules à la demande(2017)

Subjects
CORTEX, KINASE RHO-KINASE, NEURON NUMBER, genetic structures, musculoskeletal, neural, and ocular physiology, [SDV]Life Sciences [q-bio], fungi, education, Biology and Life Sciences, PROTEIN, POLYGLUTAMYLATION, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], CARBOXYPEPTIDASES, MYOSIN PHOSPHATASE, nervous system, GABAERGIC INTERNEURONS, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, AUTISM, PHOSPHORYLATION, Biology, [SDV.BDD]Life Sciences [q-bio]/Development Biology
Abstract

Interneurons navigate along multiple tangential paths to settle into appropriate cortical layers. They undergo a saltatory migration paced by intermittent nuclear jumps whose regulation relies on interplay between extracellular cues and genetic-encoded information. It remains unclear how cycles of pause and movement are coordinated at the molecular level. Post-translational modification of proteins contributes to cell migration regulation. The present study uncovers that carboxypeptidase 1, which promotes post-translational protein deglutamylation, controls the pausing of migrating cortical interneurons. Moreover, we demonstrate that pausing during migration attenuates movement simultaneity at the population level, thereby controlling the flow of interneurons invading the cortex. Interfering with the regulation of pausing not only affects the size of the cortical interneuron cohort but also impairs the generation of age-matched projection neurons of the upper layers.

Published
2018
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6. A key function for microtubule-associated-protein 6 in activity-dependent stabilisation of actin filaments in dendritic spines

Author

Peris, Leticia, Bisbal, Mariano, Martinez-Hernandez, Jose, Saoudi, Yasmina, Jonckheere, Julie, Rolland, Marta, Sebastien, Muriel, Brocard, Jacques, Denarier, Eric, Bosc, Christophe, Guérin, Christophe, Gory-Faure, Sylvie, Deloulme, Jean Christophe, Lante, Fabien, Arnal, Isabelle, Buisson, Alain, Goldberg, Yves, Blanchoin, Laurent, Delphin, Christian, Andrieux, Annie, Institut Neurosciences, Université Grenoble Alpes (UGA), Institut National de la Santé et de la Recherche Médicale (INSERM), Instituto de Investigación Médica Mercedes y Martín Ferreyra [Córdoba] (INIMEC), Universidad Nacional de Córdoba [Argentina]-Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), Biochemistry and Molecular Biology Department, University of the Basque Country (University of the Basque Country), Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV) (BIG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes (UGA), Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Physiologie cellulaire et végétale (LPCV), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), INSERM, CEA, Universite Grenoble Alpes, Photonic Imaging Center of Grenoble Institute Neuroscience (Univ Grenoble Alpes - Inserm U1216) which is part of the ISdV core facility, French Ministry for Research and Higher Education, AFM-Telethon, Region Auvergne Rhones Alpes, French ANR - Awards 2010 Blanc 120201 CBioS, ANR: 2011-MALZ-001-0217,MALAAD, ANR-17-CE11-0026,MAMAs,Coordination des microtubules et de l'actine par les MAPs structurales(2017), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), ANR-10-BLAN-1202,CBioS,Fonctions cellulaires des protéines STOP : vers une compréhension fonctionnelle et moléculaire du rôle des microtubules dans la transmission synaptique et l'organisation neuronale(2010), ANR-11-MALZ-0001,MAALAD,Perturbation du cytosquelette dans la maladie d'Alzheimer : étude cellulaire et moléculaire(2011), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
Dendritic Spines, Science, [SDV]Life Sciences [q-bio], Mice, Transgenic, macromolecular substances, Hippocampus, Microtubules, Ciencias Biológicas, purl.org/becyt/ford/1 [https], actine, Biología Celular, Microbiología, Fluorescence Resonance Energy Transfer, Animals, Humans, lcsh:Science, purl.org/becyt/ford/1.6 [https], protéine int 6, Cells, Cultured, Actin, Mice, Knockout, Neurons, Photobleaching, phosphorylation, Dendrites, Mice, Inbred C57BL, Actin Cytoskeleton, filament, MAP6, lcsh:Q, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Microtubule-Associated Proteins, actin, CIENCIAS NATURALES Y EXACTAS, microtubule
Abstract

Emerging evidence indicates that microtubule-associated proteins (MAPs) are implicated in synaptic function; in particular, mice deficient for MAP6 exhibit striking deficits in plasticity and cognition. How MAP6 connects to plasticity mechanisms is unclear. Here, we address the possible role of this protein in dendritic spines. We find that in MAP6-deficient cortical and hippocampal neurons, maintenance of mature spines is impaired, and can be restored by expressing a stretch of the MAP6 sequence called Mc modules. Mc modules directly bind actin filaments and mediate activity-dependent stabilisation of F-actin in dendritic spines, a key event of synaptic plasticity. In vitro, Mc modules enhance actin filament nucleation and promote the formation of stable, highly ordered filament bundles. Activity-induced phosphorylation of MAP6 likely controls its transfer to the spine cytoskeleton. These results provide a molecular explanation for the role of MAP6 in cognition, enlightening the connection between cytoskeletal dysfunction, synaptic impairment and neuropsychiatric illnesses. Fil: Peris, Leticia. Universite Grenoble Alpes; Francia Fil: Bisbal, Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Universite Grenoble Alpes; Francia Fil: Martinez Hernandez, José. Universidad del País Vasco; España. Universite Grenoble Alpes; Francia Fil: Saoudi, Yasmina. Universite Grenoble Alpes; Francia Fil: Jonckheere, Julie. Universite Grenoble Alpes; Francia Fil: Rolland, Marta. Universite Grenoble Alpes; Francia Fil: Sebastien, Muriel. Universite Grenoble Alpes; Francia Fil: Brocard, Jacques. Universite Grenoble Alpes; Francia Fil: Denarier, Eric. Universite Grenoble Alpes; Francia Fil: Bosc, Christopher. Universite Grenoble Alpes; Francia Fil: Guerin, Christophe. Universite Grenoble Alpes; Francia. Inserm; Francia Fil: Gory Fauré, Sylvie. Universite Grenoble Alpes; Francia Fil: Deloulme, Jean Christophe. Universite Grenoble Alpes; Francia Fil: Lanté, Fabien. Universite Grenoble Alpes; Francia Fil: Arnal, Isabelle. Universite Grenoble Alpes; Francia Fil: Buisson, Alain. Universite Grenoble Alpes; Francia Fil: Goldberg, Yves. Universite Grenoble Alpes; Francia Fil: Blanchoin, Laurent. Inserm; Francia. Universite Grenoble Alpes; Francia Fil: Delphin, Christian. Universite Grenoble Alpes; Francia Fil: Andrieux, Annie. Universite Grenoble Alpes; Francia

Published
2018
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7. MAP6 interacts with Tctex1 and Cav 2.2/N-type calcium channels to regulate calcium signalling in neurons

Author

Brocard, Jacques, Dufour, Fabrice, Gory‐Fauré, Sylvie, Arnoult, Christophe, Bosc, Christophe, Denarier, Eric, Peris, Leticia, Saoudi, Yasmina, De Waard, Michel, Andrieux, Annie, Physiopathologie du Cytosquelette, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), INSERM U836, équipe 1, Physiopathologie du cytosquelette, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Inserm, U1216, Grenoble, France., Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Groupe Physiopathologie du Cytosquelette (GPC), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)

Subjects
Mice, Knockout, Neurons, vesicles, Binding Sites, yeast two-hybrid, hippocampal neurons, [SDV]Life Sciences [q-bio], Dyneins, in vitro interactions, Molecular and Synaptic Mechanisms, plasma membrane, Hippocampus, microtubules, Mice, Calcium Channels, N-Type, Animals, Female, Calcium Signaling, yeast two‐hybrid, Microtubule-Associated Proteins, Cells, Cultured, Protein Binding
Abstract

International audience; MAP6 proteins were first described as microtubule-stabilizing agents, whose properties were thought to be essential for neuronal development and maintenance of complex neuronal networks. However, deletion of all MAP6 isoforms in MAP6 KO mice does not lead to dramatic morphological aberrations of the brain but rather to alterations in multiple neurotransmissions and severe behavioural impairments. A search for protein partners of MAP6 proteins identified Tctex1 - a dynein light chain with multiple non-microtubule-related functions. The involvement of Tctex1 in calcium signalling led to investigate it in MAP6 KO neurons. In this study, we show that functional Cav 2.2/N-type calcium channels are deficient in MAP6 KO neurons, due to improper location. We also show that MAP6 proteins interact directly with both Tctex1 and the C-terminus of Cav 2.2/N-type calcium channels. A balance of these two interactions seems to be crucial for MAP6 to modulate calcium signalling in neurons.

Published
2017
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8. CAP-Gly proteins contribute to microtubule-dependent trafficking via interactions with the C-terminal aromatic residue of α-tubulin

Author

Andrieux, Annie, Aubry, Laurence, Boscheron, Cécile, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Bertacchi Griffi, Nathalie

Subjects
p150Glued, [SDV]Life Sciences [q-bio], fungi, Brief Report - Commissioned, Biological Transport, [SDV] Life Sciences [q-bio], microtubules, trafficking, Tubulin, +Tips tyrosination, Animals, Humans, CLIP170, endosome, Microtubule-Associated Proteins, ComputingMilieux_MISCELLANEOUS
Abstract

SUMMARY In mammals, the C-terminal tyrosine residue of α-tubulin is subjected to removal/re-addition cycles resulting in tyrosinated microtubules and detyrosinated Glu-microtubules. CLIP170 and its yeast ortholog (Bik1) interact weakly with Glu-microtubules. Recently, we described a Microtubule- Rho1- and Bik1-dependent mechanism involved in Snc1 routing. Here, we further show a contribution of the yeast p150Glued ortholog (Nip100) in Snc1 trafficking. Both CLIP170 and p150Glued are CAP-Gly-containing proteins that belong to the microtubule +end-tracking protein family (known as +Tips). We discuss the +Tips-dependent role of microtubules in trafficking, the role of CAP-Gly proteins as possible molecular links between microtubules and vesicles, as well as the contribution of the Rho1-GTPase to the regulation of the +Tips repertoire and the partners associated with microtubules.

Published
2017
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9. New horizons in schizophrenia treatment: autophagy protection is coupled with behavioral improvements in a mouse model of schizophrenia

Author

Merenlender-Wagner, Avia, Shemer, Zeev, Touloumi, Olga, Lagoudaki, Rosa, Giladi, Eliezer, Andrieux, Annie, Grigoriadis, Nikolaos, Gozes, Illana, Andrieux, Annie, The Adams Super Center for Brain Studies, Tel Aviv University (TAU), The Elton Laboratory for Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, Department of Neurology and Laboratory of Experimental Neurology, AHEPA University General Hospital [Thessaloniki], Physiopathologie du Cytosquelette, [GIN] Grenoble Institut des Neurosciences (GIN), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Abstract

International audience; Autophagy plays a key role in the pathophysiology of schizophrenia as manifested by a 40% decrease in BECN1/Beclin 1 mRNA in postmortem hippocampal tissues relative to controls. This decrease was coupled with the deregulation of the essential ADNP (activity-dependent neuroprotector homeobox), a binding partner of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 beta) another major constituent of autophagy. The drug candidate NAP (davunetide), a peptide fragment from ADNP, enhanced the ADNP-LC3B interaction. Parallel genetic studies have linked allelic variation in the gene encoding MAP6/STOP (microtubule-associated protein 6) to schizophrenia, along with altered MAP6/STOP protein expression in the schizophrenic brain and schizophrenic-like behaviors in Map6-deficient mice. In this study, for the first time, we reveal significant decreases in hippocampal Becn1 mRNA and reversal by NAP but not by the antipsychotic clozapine (CLZ) in Map6-deficient (Map6+/-) mice. Normalization of Becn1 expression by NAP was coupled with behavioral protection against hyperlocomotion and cognitive deficits measured in the object recognition test. CLZ reduced hyperlocomotion below control levels and did not significantly affect object recognition. The combination of CLZ and NAP resulted in normalized outcome behaviors. Phase II clinical studies have shown NAP-dependent augmentation of functional activities of daily living coupled with brain protection. The current studies provide a new mechanistic pathway and a novel avenue for drug development.

Published
2014
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10. Tau antagonizes end-binding protein tracking at microtubule ends through a phosphorylation- dependent mechanism

Author

Ramirez-Rios, Sacnicte, Denarier, Eric, Prezel, Elea, Vinit, Angélique, Stoppin-Mellet, Virginie, Devred, François, Barbier, Pascale, Peyrot, Vincent, Sayas, Carmen Laura, Avila, Jesús, Peris, Leticia, Andrieux, Annie, Serre, Laurence, Fourest-Lieuvin, Anne, Arnal, Isabelle, Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Laboratory of Developmental Biology, McGill University, INSERM U836, équipe 1, Physiopathologie du cytosquelette, Groupe Physiopathologie du Cytosquelette (GPC), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire de physiologie cellulaire végétale (LPCV), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidad de La Laguna [Tenerife - SP] (ULL), CBM Severo Ochoa, Universidad Autonoma de Madrid (UAM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des Protéines Membranaires (LPM), Institut de biologie structurale (IBS - UMR 5075), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), McGill University = Université McGill [Montréal, Canada], Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Grenoble Institut des Neurosciences (GIN), Universidad Autónoma de Madrid (UAM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)

Subjects
phosphorylation, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, mental disorders, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, tau, EB1, microtubule
Abstract

International audience; Proper regulation of microtubule dynamics is essential for cell functions and involves various microtubule-associated proteins (MAPs). Among them, end-binding proteins (EBs) accumulate at microtubule plus ends, whereas structural MAPs bind along the microtu-bule lattice. Recent data indicate that the structural MAP tau modulates EB subcellular local-ization in neurons. However, the molecular determinants of EB/tau interaction remain unknown , as is the effect of this interplay on microtubule dynamics. Here we investigate the mechanisms governing EB/tau interaction in cell-free systems and cellular models. We find that tau inhibits EB tracking at microtubule ends. Tau and EBs form a complex via the C-terminal region of EBs and the microtubule-binding sites of tau. These two domains are required for the inhibitory activity of tau on EB localization to microtubule ends. Moreover, the phos-phomimetic mutation S262E within tau microtubule-binding sites impairs EB/tau interaction and prevents the inhibitory effect of tau on EB comets. We further show that microtubule dynamic parameters vary, depending on the combined activities of EBs and tau proteins. Overall our results demonstrate that tau directly antagonizes EB function through a phos-phorylation-dependent mechanism. This study highlights a novel role for tau in EB regulation, which might be impaired in neurodegenerative disorders.

Published
2016
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11. Tau co-organizes dynamic microtubule and actin networks

Author

Elie, Auréliane, Prezel, Elea, Guérin, Christophe, Denarier, Eric, Ramirez-Rios, Sacnicte, Serre, Laurence, Andrieux, Annie, Fourest-Lieuvin, Anne, Blanchoin, Laurent, Arnal, Isabelle, Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire de physiologie cellulaire végétale (LPCV), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Groupe Physiopathologie du Cytosquelette (GPC), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pre-doctoral fellowships from the Région Rhône-Alpes (Program 'Cible 2011')- Fondation pour la Recherche Médicale (FDT20140930826)- Post-doctoral fellowships from the Université Joseph Fourier (Grenoble), ANR-11-MALZ-0001,MAALAD,Perturbation du cytosquelette dans la maladie d'Alzheimer : étude cellulaire et moléculaire(2011), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), [GIN] Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Martin-Laffon, Jacqueline, and Maladie d'Alzheimer et Maladies Apparentées - Perturbation du cytosquelette dans la maladie d'Alzheimer : étude cellulaire et moléculaire - - MAALAD2011 - ANR-11-MALZ-0001 - MALZ - VALID

Subjects
Protein Conformation, protéine associee, Microtubule associated protein, tau Proteins, macromolecular substances, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, polymérisation, Microtubules, Nervous System, Article, Polymerization, actine, Motion, cytosquelette, neurone, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], système nerveux, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cytoskeleton, Neurons, Binding Sites, Neurosciences, neurons, cytoskeleton, microtubule/actin crosslinking, polymerization, microtubule associated protein, nervous system, tau protein, Tau Protein, Actins, Actin Cytoskeleton, Cross-Linking Reagents, Neurons and Cognition, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], microtubule, Protein Binding
Abstract

International audience; The crosstalk between microtubules and actin is essential for cellular functions. However, mechanisms underlying the microtubule-actin organization by cross-linkers remain largely unexplored. Here, we report that tau, a neuronal microtubule-associated protein, binds to microtubules and actin simultaneously, promoting in vitro co-organization and coupled growth of both networks. By developing an original assay to visualize concomitant microtubule and actin assembly, we show that tau can induce guided polymerization of actin filaments along microtubule tracks and growth of single microtubules along actin filament bundles. Importantly, tau mediates microtubule-actin co-alignment without changing polymer growth properties. Mutagenesis studies further reveal that at least two of the four tau repeated motifs, primarily identified as tubulin-binding sites, are required to connect microtubules and actin. Tau thus represents a molecular linker between microtubule and actin networks, enabling a coordination of the two cytoskeletons that might be essential in various neuronal contexts.

Published
2015

12. Both chronic treatments by epothilone D and fluoxetine increase the short-term memory and differentially alter the mood status of STOP/MAP6 KO mice

Author

Fournet, Vincent, de Lavilléon, Gaetan, Schweitzer, Annie, Giros, Bruno, Andrieux, Annie, Martres, Marie-Pascale, INSERM U836, équipe 1, Physiopathologie du cytosquelette, Physiopathologie des Maladies du Système Nerveux Central, 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)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Physiopathologie du Cytosquelette (GPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), Grants from INSERM and Université Pierre et Marie Curie, MENESR, and Andrieux, Annie

Subjects
antidepressant, MESH: Depression, corticosterone, serotonin/norepinephrine transporters, MESH: Affect, MESH: Mice, Knockout, MESH: Male, MESH: Memory, Short-Term, MESH: Serotonin Uptake Inhibitors, stress, MESH: Mice, 129 Strain, MESH: Microtubule-Associated Proteins, microtubule-stabilizing compound, MESH: Mice, Inbred C57BL, MESH: Antineoplastic Agents, MESH: Fluoxetine, MESH: Animals, MESH: Epothilones, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Disease Models, Animal, anxiety/depression, MESH: Mice, MESH: Female
Abstract

International audience; Recent evidence underlines the crucial role of neuronal cytoskeleton in the pathophysiology of psychiatric diseases. In this line, the deletion of STOP/MAP6 (Stable Tubule Only Polypeptide), a microtubule-stabilizing protein, triggers various neurotransmission and behavioral defects, suggesting that STOP knockout (KO) mice could be a relevant experimental model for schizoaffective symptoms. To establish the predictive validity of such a mouse line, in which the brain serotonergic tone is dramatically imbalanced, the effects of a chronic fluoxetine treatment on the mood status of STOP KO mice were characterized. Moreover, we determined the impact, on mood, of a chronic treatment by epothilone D, a taxol-like microtubule-stabilizing compound that has previously been shown to improve the synaptic plasticity deficits of STOP KO mice. We demonstrated that chronic fluoxetine was either antidepressive and anxiolytic, or pro-depressive and anxiogenic, depending on the paradigm used to test treated mutant mice. Furthermore, control-treated STOP KO mice exhibited paradoxical behaviors, compared with their clear-cut basal mood status. Paradoxical fluoxetine effects and control-treated STOP KO behaviors could be because of their hyper-reactivity to acute and chronic stress. Interestingly, both epothilone D and fluoxetine chronic treatments improved the short-term memory of STOP KO mice. Such treatments did not affect the serotonin and norepinephrine transporter densities in cerebral areas of mice. Altogether, these data demonstrated that STOP KO mice could represent a useful model to study the relationship between cytoskeleton, mood, and stress, and to test innovative mood treatments, such as microtubule-stabilizing compounds.

Published
2012
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13. MAP6-F is a temperature sensor that directly binds to and protects microtubules from cold-induced depolymerization

Author

Delphin, Christian, Bouvier, Denis, Seggio, Maxime, Couriol, Emilie, Saoudi, Yasmina, Denarier, Eric, Bosc, Christophe, Valiron, Odile, Bisbal, Mariano, Arnal, Isabelle, Andrieux, Annie, INSERM U836, équipe 1, Physiopathologie du cytosquelette, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), European Molecular Biology Laboratory [Grenoble] (EMBL), Groupe Physiopathologie du Cytosquelette (GPC), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), INSERM U836, équipe 13, Régulation dynamique et structurale du cytosquelette, INSERM, CEA, University Joseph Fourier, Roche Pharmaceutic RPF program., and Andrieux, Annie

Subjects
MESH: Humans, MESH: Cold Temperature, MESH: Microtubules, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Microtubules, MESH: Microtubule-Associated Proteins, MESH: Protein Structure, Tertiary, MAP6, MESH: HeLa Cells, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, hypothermia, MESH: Mice, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: NIH 3T3 Cells
Abstract

International audience; Microtubules are dynamic structures that present the peculiar characteristic to be ice-cold labile in vitro. In vivo, microtubules are protected from ice-cold induced depolymerization by the widely expressed MAP6/STOP family of proteins. However, the mechanism by which MAP6 stabilizes microtubules at 4 °C has not been identified. Moreover, the microtubule cold sensitivity and therefore the needs for microtubule stabilization in the wide range of temperatures between 4 and 37 °C are unknown. This is of importance as body temperatures of animals can drop during hibernation or torpor covering a large range of temperatures. Here, we show that in the absence of MAP6, microtubules in cells below 20 °C rapidly depolymerize in a temperature-dependent manner whereas they are stabilized in the presence of MAP6. We further show that in cells, MAP6-F binding to and stabilization of microtubules is temperature- dependent and very dynamic, suggesting a direct effect of the temperature on the formation of microtubule/MAP6 complex. We also demonstrate using purified proteins that MAP6-F binds directly to microtubules through its Mc domain. This binding is temperature-dependent and coincides with progressive conformational changes of the Mc domain as revealed by circular dichroism. Thus, MAP6 might serve as a temperature sensor adapting its conformation according to the temperature to maintain the cellular microtubule network in organisms exposed to temperature decrease.

Published
2012
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14. The deletion of STOP/MAP6 protein in mice triggers highly altered mood and impaired cognitive performances

Author

Fournet, Vincent, Schweitzer, Annie, Chevarin, Caroline, Deloulme, Jean-Christophe, Hamon, Michel, Giros, Bruno, Andrieux, Annie, Martres, Marie-Pascale, INSERM U836, équipe 1, Physiopathologie du cytosquelette, Physiopathologie des Maladies du Système Nerveux Central, 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)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Grenoble Institut des Neurosciences (GIN), Centre de Psychiatrie et Neurosciences (U894), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Groupe Physiopathologie du Cytosquelette (GPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), This study was supported by grants from INSERM and Universite' Pierre et Marie Curie. Vincent Fournet is the recipient of fellowships from the MENESR (France)., Institut de psychiatrie et neurosciences (U894 / UMS 1266), Andrieux, Annie, 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 ) -Grenoble Institut des Neurosciences ( GIN ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Grenoble Institut des Neurosciences ( GIN ), Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), 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 ), Groupe Physiopathologie du Cytosquelette ( GPC-GIN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Grenoble Institut des Neurosciences ( GIN ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Grenoble, Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Grenoble Institut des Neurosciences (GIN)

Subjects
MESH: Mood Disorders, MESH : Male, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Mice, Inbred BALB C, MESH : Gene Deletion, MESH : Mice, Inbred C57BL, MESH : Behavior, Animal, MESH: Mice, Knockout, MESH : Mice, 129 Strain, MESH : Cognition Disorders, MESH: Mice, 129 Strain, MESH: Mice, Inbred C57BL, MESH : Mice, MESH: Behavior, Animal, MESH : Female, MESH: Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Nerve Tissue Proteins, MESH : Nerve Tissue Proteins, MESH: Mice, MESH : Mice, Inbred BALB C, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Male, MESH: Microtubule-Associated Proteins, MESH: Cognition Disorders, MESH : Microtubule-Associated Proteins, MESH: Gene Deletion, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH : Mice, Knockout, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH : Animals, MESH : Mood Disorders, MESH: Female
Abstract

International audience; The microtubule-associated Stable Tubulie Only Polypeptide (STOP; also known as MAP6) protein plays a key role in neuron architecture and synaptic plasticity, the dysfunctions of which are thought to be implicated in the pathophysiology of psychiatric diseases. The deletion of STOP in mice leads to severe disorders reminiscent of several schizophrenia-like symptoms, which are also associated with differential alterations of the serotonergic tone in somas versus terminals. In STOP knockout (KO) compared with wild-type mice, serotonin (5-HT) markers are found to be markedly accumulated in the raphe nuclei and, in contrast, deeply depleted in all serotonergic projection areas. In the present study, we carefully examined whether the 5-HT imbalance would lead to behavioral consequences evocative of mood and/or cognitive disorders. We showed that STOP KO mice exhibited depression-like behavior, associated with a decreased anxiety-status in validated paradigms. In addition, although STOP KO mice had a preserved very short-term memory, they failed to perform well in all other learning and memory tasks. We also showed that STOP KO mice exhibited regional imbalance of the norepinephrine tone as observed for 5-HT. As a consequence, mutant mice were hypersensitive to acute antidepressants with different selectivity. Altogether, these data indicate that the deletion of STOP protein in mice caused deep alterations in mood and cognitive performances and that STOP protein might have a crucial role in the 5-HT and norepinephrine networks development.

Published
2012
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15. Reduced Expression of STOP/MAP6 in Mice Leads to Cognitive Deficits

Author

Volle, Julien, Brocard, Jacques, Saoud, Mohamed, Gory-Faure, Sylvie, Brunelin, Jérôme, Andrieux, Annie, Suaud-Chagny, Marie-Françoise, Andrieux, Annie, Schizophrenies Débutantes et Résistantes : de la Physiopathologie à la Thérapeutique, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, INSERM U836, équipe 1, Physiopathologie du cytosquelette, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier le Vinatier [Bron], Groupe Physiopathologie du Cytosquelette (GPC), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), and Région Rhône-Alpes France ('Cluster 11: Age-Handicap-Vieillissement')

Subjects
behavioural phenotype, neurodevelopment, animal model, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, gene x environment interaction, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Schizophrenia, microtubule
Abstract

International audience; Background: STOP/MAP6 null (KO) mice recapitulate behavioral abnormalities related to positive and negative symptoms and cognitive deficits of schizophrenia. Here, we investigated whether decreased expression of STOP/MAP6 proteins in heterozygous mice (only one allele expressed) would result in abnormal behavior related to those displayed by STOP null mice. Methods : Using a comprehensive test battery, we investigated the behavioral phenotype of STOP heterozygous (Het) mice compared with STOP KO and wild type (WT) mice on animals raised either in standard conditions (controls) or submitted to maternal deprivation. Results : Control Het mice displayed prominent deficits in social interaction and learning, resembling KO mice. In contrast, they exhibited short-lasting locomotor hyperreactivity to acute mild stress and no impaired locomotor response to amphetamine, much like WT mice. Additionally, perinatal stress deteriorated Het mouse phenotype by exacerbating alterations related to positive symptoms such as their locomotor reactivity to acute mild stress and psychostimulant challenge. Conclusion : Results show that the dosage of susceptibility genes modulates their putative phenotypic contribution and that STOP expression has a high penetrance on cognitive abilities. Hence, STOP Het mice might be useful to investigate cognitive defects related to those observed in mental diseases and ultimately might be a valuable experimental model to evaluate preventive treatments.

Published
2012
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16. [Microtubule polyglutamylation and neurodegeneration]

Author

Moutin, Marie-Jo, Andrieux, Annie, Janke, Carsten, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Signalisation, neurobiologie et cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Andrieux, Annie, and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Humans, MESH: Serine-Type D-Ala-D-Ala Carboxypeptidase, MESH: Microtubules, MESH: Molecular Motor Proteins, MESH: Tubulin, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Axoneme, MESH: Peptide Synthases, MESH: Eukaryotic Cells, MESH: Flagella, MESH: Nerve Degeneration, MESH: Cell Survival, MESH: Cilia, MESH: Models, Neurological, MESH: Protein Processing, Post-Translational, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Nerve Tissue Proteins, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS
Abstract

International audience; n.a

Published
2011
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17. The deletion of the microtubule-associated STOP protein affects the serotonergic mouse brain network

Author

Fournet, Vincent, Jany, Marion, Fabre, Véronique, Chali, Farah, Orsal, Didier, Schweitzer, Annie, Andrieux, Annie, Messanvi, Fany, Giros, Bruno, Hamon, Michel, Lanfumey, Laurence, Deloulme, Jean-Christophe, Martres, Marie-Pascale, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie des Maladies du Système Nerveux Central, 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), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), 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), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM MENESR (Paris, France), Grenoble Institut des Neurosciences ( GIN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Grenoble-Université Joseph Fourier - Grenoble 1 ( UJF ), 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 ), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Psychiatrie et Neurosciences (U894), and Andrieux, Annie

Subjects
MESH : Serotonin, MESH : Male, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Mice, Inbred BALB C, MESH: Mice, Knockout, MESH : Mice, 129 Strain, MESH : Maze Learning, MESH: Brain, MESH: Mice, 129 Strain, MESH : Mice, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Female, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, MESH : Mice, Inbred BALB C, MESH: Maze Learning, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Male, MESH: Microtubule-Associated Proteins, MESH : Brain, MESH: Nerve Net, MESH : Microtubule-Associated Proteins, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH : Nerve Net, MESH : Mice, Knockout, MESH: Serotonin, MESH : Animals, MESH: Female
Abstract

International audience; The deletion of microtubule-associated protein stable tubule only polypeptide (STOP) leads to neuroanatomical, biochemical and severe behavioral alterations in mice, partly alleviated by antipsychotics. Therefore, STOP knockout (KO) mice have been proposed as a model of some schizophrenia-like symptoms. Preliminary data showed decreased brain serotonin (5-HT) tissue levels in STOP KO mice. As literature data demonstrate various interactions between microtubule-associated proteins and 5-HT, we characterized some features of the serotonergic neurotransmission in STOP KO mice. In the brainstem, mutant mice displayed higher tissue 5-HT levels and in vivo synthesis rate, together with marked increases in 5-HT transporter densities and 5-HT1A autoreceptor levels and electrophysiological sensitivity, without modification of the serotonergic soma number. Conversely, in projection areas, STOP KO mice exhibited lower 5-HT levels and in vivo synthesis rate, associated with severe decreases in 5-HT transporter densities, possibly related to reduced serotonergic terminals. Mutant mice also displayed a deficit of adult hippocampal neurogenesis, probably related to both STOP deletion and 5-HT depletion. Finally, STOP KO mice exhibited a reduced anxiety- and, probably, an increased helpness-status, that could be because of the strong imbalance of the serotonin neurotransmission between somas and terminals. Altogether, these data suggested that STOP deletion elicited peculiar 5-HT disconnectivity.

Published
2010
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18. Impact of manganese on primary hippocampal neurons from rodents

Author

Daoust, Alexia, Saoudi, Yasmina, Brocard, Jacques, Collomb, Nora, Batandier, Cécile, Bisbal, Mariano, Salomé, Murielle, Andrieux, Annie, Bohic, Sylvain, Barbier, Emmanuel, Neuro-imagerie fonctionnelle et métabolique (ANTE-INSERM U836, équipe 5), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U836, équipe 1, Physiopathologie du cytosquelette, Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), INSERM U836, équipe 6, Rayonnement synchrotron et recherche médicale, European Synchrotron Radiation Facility (ESRF)-Grenoble Institut des Neurosciences (GIN), Région Rhône-Alpes - Cluster HVN., Dojat, Michel, and Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Neurons, Time Factors, Dose-Response Relationship, Drug, Otras Ciencias Biológicas, hippocampal neurons, Spectrometry, X-Ray Emission, MEMRI, Phosphorus, Hippocampus, Trace Elements, Ciencias Biológicas, mitochondria, Mice, Neuroblastoma, Zinc, hippocampalneurons, manganese, Animals, X-ray synchrotron, Calcium, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cells, Cultured, CIENCIAS NATURALES Y EXACTAS
Abstract

Manganese-enhanced magnetic resonance imaging (MEMRI) is a powerful tool for in vivo tract tracing or functional imaging of the central nervous system. However Mn2+ may be toxic at high levels. In this study, we addressed the impact of Mn2+ on mouse hippocampal neurons (HN) and neuron-like N2a cells in culture, using several approaches. Both HN and N2a cells not exposed to exogenous MnCl2 were shown by synchrotron X-ray fluorescence to contain 5 mg/g Mn. Concentrations of Mn2+ leading to 50% lethality (LC50) after 24 h of incubation were much higher for N2a cells (863 mM) than for HN (90 mM). The distribution of Mn2+ in both cell types exposed to Mn2+ concentrations below LC50 was perinuclear whereas that in cells exposed to concentrations above LC50 was more diffuse, suggesting an overloading of cell storage/detoxification capacity. In addition, Mn2+ had a cell-type and dose-dependent impact on the total amount of intracellular P, Ca, Fe and Zn measured by synchrotron X-ray fluorescence. For HN neurons, immunofluorescence studies revealed that concentrations of Mn2+ below LC50 shortened neuritic length and decreased mitochondria velocity after 24 h of incubation. Similar concentrations of Mn2+ also facilitated the opening of the mitochondrial permeability transition pore in isolated mitochondria from rat brains. The sensitivity of primary HN to Mn2+ demonstrated here supports their use as a relevant model to study Mn2+-induced neurotoxicity. Fil: Daoust, Alexia. Inserm; Francia. Université Grenoble Alpes. Grenoble; Francia Fil: Saoudi, Yasmina. Université Grenoble Alpes. Grenoble; Francia. Inserm; Francia Fil: Brocard, Jacques. Université Grenoble Alpes. Grenoble; Francia. Inserm; Francia Fil: Collomb, Nora. Université Grenoble Alpes. Grenoble; Francia. Inserm; Francia Fil: Batandier, Cecile. Laboratoire de Bioénergétique. Grenoble; Francia Fil: Bisbal, Mariano. Université Grenoble Alpes. Grenoble; Francia. Inserm; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Salomé, Murielle. European Synchrotron Radiation Facility. Grenoble; Francia Fil: Andrieux, Annie. Université Grenoble Alpes. Grenoble; Francia. Inserm; Francia Fil: Bohic, Sylvain. European Synchrotron Radiation Facility. Grenoble; Francia. Université Grenoble Alpes. Grenoble; Francia. Inserm; Francia Fil: Barbier , Emmanuel. Université Grenoble Alpes. Grenoble; Francia. Inserm; Francia

Published
2014
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19. New horizons in schizophrenia treatment: autophagy protection is coupled with behavioral improvements in a mouse model of schizophrenia

Author

Merenlender-Wagner, Avia, Shemer, Zeev, Touloumi, Olga, Lagoudaki, Rosa, Giladi, Eliezer, Andrieux, Annie, Grigoriadis, Nikolaos, Gozes, Illana, The Adams Super Center for Brain Studies, Tel Aviv University [Tel Aviv], The Elton Laboratory for Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, Department of Neurology and Laboratory of Experimental Neurology, AHEPA University General Hospital [Thessaloniki], Physiopathologie du Cytosquelette, [GIN] Grenoble Institut des Neurosciences (GIN), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)

Subjects
[SDV]Life Sciences [q-bio], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Abstract

International audience; Autophagy plays a key role in the pathophysiology of schizophrenia as manifested by a 40% decrease in BECN1/Beclin 1 mRNA in postmortem hippocampal tissues relative to controls. This decrease was coupled with the deregulation of the essential ADNP (activity-dependent neuroprotector homeobox), a binding partner of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 beta) another major constituent of autophagy. The drug candidate NAP (davunetide), a peptide fragment from ADNP, enhanced the ADNP-LC3B interaction. Parallel genetic studies have linked allelic variation in the gene encoding MAP6/STOP (microtubule-associated protein 6) to schizophrenia, along with altered MAP6/STOP protein expression in the schizophrenic brain and schizophrenic-like behaviors in Map6-deficient mice. In this study, for the first time, we reveal significant decreases in hippocampal Becn1 mRNA and reversal by NAP but not by the antipsychotic clozapine (CLZ) in Map6-deficient (Map6+/-) mice. Normalization of Becn1 expression by NAP was coupled with behavioral protection against hyperlocomotion and cognitive deficits measured in the object recognition test. CLZ reduced hyperlocomotion below control levels and did not significantly affect object recognition. The combination of CLZ and NAP resulted in normalized outcome behaviors. Phase II clinical studies have shown NAP-dependent augmentation of functional activities of daily living coupled with brain protection. The current studies provide a new mechanistic pathway and a novel avenue for drug development.

Published
2014
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20. Deletion of the STOP gene, a microtubule stabilizing factor, leads only to discrete cerebral metabolic changes in mice

Author

Hanaya, Ryosuke, Koning, Estelle, Ferrandon, Arielle, Schweitzer, Annie, Andrieux, Annie, Nehlig, Astrid, Physiopathologie clinique et expérimentale de la schizophrénie, Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), Organisation Fonctionnelle du Cytosquelette, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR27, The present study was supported by grants from the Institut National de la Santé et de la Recherche Médicale (INSERM U 366, 405 and 666) and from the Fondation pour la Recherche Médicale., Collaboration, and Andrieux, Annie

Subjects
cytoskeleton, transgenic mice, cerebral glucose metabolism, MESH: Mice, Knockout, MESH: Male, microtubules, schizophrenia, MESH: Glucose, MESH: Brain, MESH: Microtubule-Associated Proteins, STOP protein, MESH: Autoradiography, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Animals, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Mice
Abstract

International audience; In mice, deletion of the STOP protein leads to subtle anatomic changes and induces depleted synaptic vesicle pools, impaired synaptic plasticity, hyperdopaminergy, and major behavioral disorders alleviated by neuroleptics, hence leading to a schizophrenic-like phenotype. In this study, we applied the quantitative autoradiographic [(14)C]2-deoxyglucose technique to study to what extent the basal rate of cerebral glucose utilization in STOP-knockout (STOP-KO) mice occurs in regions where metabolic changes have been reported in schizophrenic patients. Studies were performed on wild-type, heterozygous, and homozygous STOP-KO mice (7-8 per group). Mice were implanted with femoral artery and vein catheters, and cerebral glucose utilization was quantified over 45 min. Compared with that in wild-type mice, glucose utilization in STOP-KO mice was significantly increased in the olfactory cortex, ventromedial and anterolateral hypothalamus, ventral tegmental area, and substantia nigra pars compacta. Nonsignificant increases, ranging between 9% and 19%, were recorded in the whole auditory system, CA1 pyramidal cell layer, and dorsal raphe. Glucose utilization was also significantly increased in heterozygous mice compared with that in wild-type mice in olfactory cortex. These data might reflect hyperdopaminergic activity, olfactory deficits, and sleep disturbances in STOP-KO mice that have also been reported in schizophrenic patients.

Published
2008
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21. Microtubule-associated STOP protein deletion triggers restricted changes in dopaminergic neurotransmission.: Accumbic DA system in STOP KO mice

Author

Bouvrais-Veret, Caroline, Weiss, Stéphanie, Hanoun, Naima, Andrieux, Annie, Schweitzer, Annie, Job, Didier, Hamon, Michel, Giros, Bruno, Martres, Marie-Pascale, Andrieux, Annie, Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Neuropsychopharmacologie [CHU Pitié-Salpétriêre], 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupe Physiopathologie du Cytosquelette (GPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM, and Collaboration

Subjects
MESH: Dopamine Uptake Inhibitors, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Mice, Inbred BALB C, cocaine, MESH: Vesicular Monoamine Transport Proteins, MESH: Dopamine, dopaminergic transporter and receptors, MESH: Mice, Knockout, MESH: Dose-Response Relationship, Drug, MESH: Basal Ganglia, MESH: Cocaine, tyrosine hydroxylase, MESH: Analysis of Variance, MESH: Synaptic Transmission, MESH: Receptors, Dopamine, MESH: Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Radiography, MESH: Tyrosine 3-Monooxygenase, MESH: Mice, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, synaptosomes, cytoskeleton, MESH: Motor Activity, schizophrenia, MESH: Microtubule-Associated Proteins, MESH: Synaptosomes, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Abstract

International audience; The microtubule-associated stable tubule only polypeptide (STOP) protein plays a key-role in neuron architecture and synaptic plasticity. Recent studies suggest that schizophrenia is associated with alterations in the synaptic connectivity. Mice invalidated for the STOP gene display phenotype reminiscent of some schizophrenic-like symptoms, such as behavioral disturbances, dopamine (DA) hyper-reactivity, and possible hypoglutamatergia, partly improved by antipsychotic treatment. In the present work, we examined potential alterations in some DAergic key proteins and behaviors in STOP knockout mice. Whereas the densities of the DA transporter, the vesicular monoamine transporter and the D(1) receptor were not modified, the densities of the D(2) and D(3) receptors were decreased in some DAergic regions in mutant versus wild-type mice. Endogenous DA levels were selectively decreased in DAergic terminals areas, although the in vivo DA synthesis was diminished both in cell bodies and terminal areas. The DA uptake was decreased in accumbic synaptosomes, but not significantly altered in striatal synaptosomes. Finally, STOP knockout mice were hypersensitive to acute and subchronic locomotor effects of cocaine, although the drug equally inhibited DA uptake in mutant and wild-type mice. Altogether, these data showed that deletion of the ubiquitous STOP protein elicited restricted alterations in DAergic neurotransmission, preferentially in the meso-limbic pathway.

Published
2008
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22. Hypoglutamatergic activity in the STOP knockout mouse: a potential model for chronic untreated schizophrenia.: 13C study of metabolism in STOP KO mice

Author

Brenner, Eiliv, Sonnewald, Ursula, Schweitzer, Annie, Andrieux, Annie, Nehlig, Astrid, Andrieux, Annie, Department of Neuroscience, Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU)-Norwegian University of Science and Technology (NTNU), Organisation Fonctionnelle du Cytosquelette, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR27, Physiopathologie clinique et expérimentale de la schizophrénie, Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), and Collaboration

Subjects
STOP KO mice, MESH: Neurons, neurons, glutamate, MESH: Dopamine, MESH: Mice, Knockout, MESH: Brain, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Brain Chemistry, MESH: Chromatography, High Pressure Liquid, MESH: Mice, MESH: Glutamine, MESH: Magnetic Resonance Spectroscopy, MESH: Chronic Disease, MESH: Energy Metabolism, astrocytes, MESH: Glutamic Acid, MESH: Synaptic Vesicles, MESH: Male, MESH: Schizophrenia, schizophrenia, MESH: Astrocytes, MESH: Microtubule-Associated Proteins, glutamine, MESH: Disease Models, Animal
Abstract

International audience; In mice, the deletion of the STOP protein leads to hyperdopaminergia and major behavioral disorders that are alleviated by neuroleptics, representing a potential model of schizophrenia. The reduction of the glutamatergic synaptic vesicle pool in the hippocampus could reflect a disturbance in glutamatergic neurotransmission in this model. Here we examined potential disturbances in energy metabolism and interactions between neurons and glia in 15-week-old STOP KO, wild-type, and heterozygous mice. Animals received [1-(13)C]glucose and [1,2-(13)C]acetate, the preferential substrates of neurons and astrocytes, respectively. Extracts from the whole forebrain and midbrain were analyzed by HPLC, (13)C and (1)H NMR spectroscopy. Amounts and labeling of most metabolites were unchanged. However, glutamine concentration and amount of [4,5-(13)C]glutamine derived from [1,2-(13)C]acetate significantly decreased by 17% and 18%, respectively, in STOP KO compared with wild-type mice. The amount of [4-(13)C]glutamate was decreased in STOP KO and heterozygous compared with wild-type mice. gamma-Aminobutyric acid labeling was not influenced by the genotype. Because STOP-deficient mice have a lower synaptic vesicle density, less glutamate is released to the synaptic cleft, leading to decreased stimulation of the postsynaptic glutamate receptors, reflecting increased glutamine metabolism only in the vicinity of the postsynapse of STOP KO mice.

Published
2007
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23. Post-translational arginylation of calreticulin: a new isospecies of calreticulin component of stress granules

Author

Decca, María, Carpio, Marcos, Bosc, Christophe, Galiano, Mauricio, Job, Didier, Andrieux, Annie, Hallak, Marta, Andrieux, Annie, Centro de Investigaciones en Química Biológica de Córdoba, Universidad Nacional de Córdoba [Argentina], Organisation Fonctionnelle du Cytosquelette, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR27, and Collaboration

Subjects
MESH: Protein Transport, Time Factors, genetic structures, MESH: Rats, MESH: Calreticulin, Arginine, Endoplasmic Reticulum, Article, Mice, MESH: Brain, Cytosol, MESH: Cytosol, MESH: Endoplasmic Reticulum, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Immunoprecipitation, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, cardiovascular diseases, MESH: Mice, MESH: Peptides, MESH: Immunoprecipitation, MESH: Time Factors, MESH: Arginine, Brain, equipment and supplies, Rats, Protein Transport, MESH: Protein Processing, Post-Translational, MESH: Calcium, NIH 3T3 Cells, cardiovascular system, Calcium, Calreticulin, Peptides, Protein Processing, Post-Translational, circulatory and respiratory physiology, MESH: NIH 3T3 Cells
Abstract

International audience; Post-translational arginylation consists of the covalent union of an arginine residue to a Glu, Asp, or Cys amino acid at the N-terminal position of proteins. This reaction is catalyzed by the enzyme arginyl-tRNA protein transferase. Using mass spectrometry, we have recently demonstrated in vitro the post-translational incorporation of arginine into the calcium-binding protein calreticulin (CRT). To further study arginylated CRT we raised an antibody against the peptide (RDPAIYFK) that contains an arginine followed by the first 7 N-terminal amino acids of mature rat CRT. This antibody specifically recognizes CRT obtained from rat soluble fraction that was arginylated in vitro and also recognizes endogenous arginylated CRT from NIH 3T3 cells in culture, indicating that CRT arginylation takes place in living cells. Using this antibody we found that arginylation of CRT is Ca2+-regulated. In vitro and in NIH 3T3 cells in culture, the level of arginylated CRT increased with the addition of a Ca2+ chelator to the medium, whereas a decreased arginine incorporation into CRT was found in the presence of Ca2+. The arginylated CRT was observed in the cytosol, in contrast to the non-arginylated CRT that is in the endoplasmic reticulum. Under stress conditions, arginylated CRT was found associated to stress granules. These results suggest that CRT arginylation occurs in the cytosolic pool of mature CRT (defined by an Asp acid N-terminal) that is probably retrotranslocated from the endoplasmic reticulum.

Published
2007
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24. Phosphorylation of microtubule-associated protein STOP by calmodulin kinase II.: Phosphorylation of STOP by CaMKII

Author

Baratier, Julie, Peris, Leticia, Brocard, Jacques, Gory-Fauré, Sylvie, Dufour, Fabrice, Bosc, Christophe, Fourest-Lieuvin, Anne, Blanchoin, Laurent, Salin, Paul, Job, Didier, Andrieux, Annie, Andrieux, Annie, Organisation Fonctionnelle du Cytosquelette, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR27, Laboratoire de physiologie cellulaire végétale (LPCV), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Physio-pathologie des réseaux neuronaux du cycle veille-sommeil, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), and This work was supported in part by grants from La Ligue Nationale contre le Cancer to D.J.

Subjects
MESH: Protein Transport, MESH: Hippocampus, MESH: Neurons, MESH: Microscopy, Fluorescence, MESH: Actins, Hippocampus, Microtubules, Fluorescence, MESH: Synapses, Mice, MESH: Brain, Calmodulin, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Calcium-Calmodulin-Dependent Protein Kinases, Animals, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Phosphorylation, MESH: Mice, Neurons, Microscopy, MESH: Phosphorylation, MESH: Microtubules, Brain, MESH: Calmodulin, Actins, Protein Transport, MESH: Microtubule-Associated Proteins, Calcium-Calmodulin-Dependent Protein Kinases, Synapses, MESH: Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Microtubule-Associated Proteins
Abstract

International audience; STOP proteins are microtubule-associated, calmodulin-regulated proteins responsible for the high degree of stabilization displayed by neuronal microtubules. STOP suppression in mice induces synaptic defects affecting both short and long term synaptic plasticity in hippocampal neurons. Interestingly, STOP has been identified as a component of synaptic structures in neurons, despite the absence of microtubules in nerve terminals, indicating the existence of mechanisms able to induce a translocation of STOP from microtubules to synaptic compartments. Here we have tested STOP phosphorylation as a candidate mechanism for STOP relocalization. We show that, both in vitro and in vivo, STOP is phosphorylated by the multifunctional enzyme calcium/calmodulin-dependent protein kinase II (CaMKII), which is a key enzyme for synaptic plasticity. This phosphorylation occurs on at least two independent sites. Phosphorylated forms of STOP do not bind microtubules in vitro and do not co-localize with microtubules in cultured differentiating neurons. Instead, phosphorylated STOP co-localizes with actin assemblies along neurites or at branching points. Correlatively, we find that STOP binds to actin in vitro. Finally, in differentiated neurons, phosphorylated STOP co-localizes with clusters of synaptic proteins, whereas unphosphorylated STOP does not. Thus, STOP phosphorylation by CaMKII may promote STOP translocation from microtubules to synaptic compartments where it may interact with actin, which could be important for STOP function in synaptic plasticity.

Published
2006
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25. Structural Basis for the Association of MAP6 Protein with Microtubules and Its Regulation by Calmodulin

Author

Lefèvre, Julien, Savarin, Philippe, Gans, Pierre, Hamon, Loïc, Clément, Marie-Jeanne, David, Marie-Odile, Bosc, Christophe, Andrieux, Annie, Curmi, Patrick, Structure et activité des biomolécules normales et pathologiques (SABNP), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Résonance Magnétique Nucléaire (LRMN), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), INSERM U836, équipe 1, Physiopathologie du cytosquelette, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Physiopathologie du Cytosquelette (GPC), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), PRES UniversSud, Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Grenoble Institut des Neurosciences (GIN)

Subjects
STOP, Calmodulin, Tubulin, MAP6, Calcium, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Microtubules, NMR, Cold
Abstract

International audience; Microtubules are highly dynamic αβ-tubulin polymers. In vitro and in living cells, microtubules are most often cold- and nocodazole-sensitive. When present, the MAP6/STOP family of proteins protects microtubules from cold- and nocodazole-induced depolymerization but the molecular and structure determinants by which these proteins stabilize microtubules remain under debate. We show here that a short protein fragment from MAP6-N, which encompasses its Mn1 and Mn2 modules (MAP6(90-177)), recapitulates the function of the full-length MAP6-N protein toward microtubules, i.e. its ability to stabilize microtubules in vitro and in cultured cells in ice-cold conditions or in the presence of nocodazole. We further show for the first time, using biochemical assays and NMR spectroscopy, that these effects result from the binding of MAP6(90-177) to microtubules with a 1:1 MAP6(90-177):tubulin heterodimer stoichiometry. NMR data demonstrate that the binding of MAP6(90-177) to microtubules involve its two Mn modules but that a single one is also able to interact with microtubules in a closely similar manner. This suggests that the Mn modules represent each a full microtubule binding domain and that MAP6 proteins may stabilize microtubules by bridging tubulin heterodimers from adjacent protofilaments or within a protofilament. Finally, we demonstrate that Ca(2+)-calmodulin competes with microtubules for MAP6(90-177) binding and that the binding mode of MAP6(90-177) to microtubules and Ca(2+)-calmodulin involves a common stretch of amino acid residues on the MAP6(90-177) side. This result accounts for the regulation of microtubule stability in cold condition by Ca(2+)-calmodulin.

Published
2013
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26. Both chronic treatments by epothilone D and fluoxetine increase the short-term memory and differentially alter the mood status of STOP/MAP6 KO mice

Author

Fournet, Vincent, de Lavilléon, Gaetan, Schweitzer, Annie, Giros, Bruno, Andrieux, Annie, Martres, Marie-Pascale, INSERM U836, équipe 1, Physiopathologie du cytosquelette, Physiopathologie des Maladies du Système Nerveux Central, 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)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Physiopathologie du Cytosquelette (GPC), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), Grants from INSERM and Université Pierre et Marie Curie, MENESR, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Grenoble Institut des Neurosciences (GIN)

Subjects
antidepressant, MESH: Depression, corticosterone, serotonin/norepinephrine transporters, MESH: Affect, MESH: Mice, Knockout, MESH: Male, MESH: Memory, Short-Term, MESH: Serotonin Uptake Inhibitors, stress, MESH: Mice, 129 Strain, MESH: Microtubule-Associated Proteins, microtubule-stabilizing compound, MESH: Mice, Inbred C57BL, MESH: Antineoplastic Agents, MESH: Fluoxetine, MESH: Animals, MESH: Epothilones, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Disease Models, Animal, anxiety/depression, MESH: Mice, MESH: Female
Abstract

International audience; Recent evidence underlines the crucial role of neuronal cytoskeleton in the pathophysiology of psychiatric diseases. In this line, the deletion of STOP/MAP6 (Stable Tubule Only Polypeptide), a microtubule-stabilizing protein, triggers various neurotransmission and behavioral defects, suggesting that STOP knockout (KO) mice could be a relevant experimental model for schizoaffective symptoms. To establish the predictive validity of such a mouse line, in which the brain serotonergic tone is dramatically imbalanced, the effects of a chronic fluoxetine treatment on the mood status of STOP KO mice were characterized. Moreover, we determined the impact, on mood, of a chronic treatment by epothilone D, a taxol-like microtubule-stabilizing compound that has previously been shown to improve the synaptic plasticity deficits of STOP KO mice. We demonstrated that chronic fluoxetine was either antidepressive and anxiolytic, or pro-depressive and anxiogenic, depending on the paradigm used to test treated mutant mice. Furthermore, control-treated STOP KO mice exhibited paradoxical behaviors, compared with their clear-cut basal mood status. Paradoxical fluoxetine effects and control-treated STOP KO behaviors could be because of their hyper-reactivity to acute and chronic stress. Interestingly, both epothilone D and fluoxetine chronic treatments improved the short-term memory of STOP KO mice. Such treatments did not affect the serotonin and norepinephrine transporter densities in cerebral areas of mice. Altogether, these data demonstrated that STOP KO mice could represent a useful model to study the relationship between cytoskeleton, mood, and stress, and to test innovative mood treatments, such as microtubule-stabilizing compounds.

Published
2012
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27. MAP6-F is a temperature sensor that directly binds to and protects microtubules from cold-induced depolymerization

Author

Delphin, Christian, Bouvier, Denis, Seggio, Maxime, Couriol, Emilie, Saoudi, Yasmina, Denarier, Eric, Bosc, Christophe, Valiron, Odile, Bisbal, Mariano, Arnal, Isabelle, Andrieux, Annie, INSERM U836, équipe 1, Physiopathologie du cytosquelette, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), European Molecular Biology Laboratory [Grenoble] (EMBL), Groupe Physiopathologie du Cytosquelette (GPC), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), INSERM U836, équipe 13, Régulation dynamique et structurale du cytosquelette, INSERM, CEA, University Joseph Fourier, and Roche Pharmaceutic RPF program.

Subjects
MESH: Humans, MESH: Cold Temperature, MESH: Microtubules, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Microtubules, MESH: Microtubule-Associated Proteins, MESH: Protein Structure, Tertiary, MAP6, MESH: HeLa Cells, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, hypothermia, MESH: Mice, MESH: NIH 3T3 Cells
Abstract

International audience; Microtubules are dynamic structures that present the peculiar characteristic to be ice-cold labile in vitro. In vivo, microtubules are protected from ice-cold induced depolymerization by the widely expressed MAP6/STOP family of proteins. However, the mechanism by which MAP6 stabilizes microtubules at 4 °C has not been identified. Moreover, the microtubule cold sensitivity and therefore the needs for microtubule stabilization in the wide range of temperatures between 4 and 37 °C are unknown. This is of importance as body temperatures of animals can drop during hibernation or torpor covering a large range of temperatures. Here, we show that in the absence of MAP6, microtubules in cells below 20 °C rapidly depolymerize in a temperature-dependent manner whereas they are stabilized in the presence of MAP6. We further show that in cells, MAP6-F binding to and stabilization of microtubules is temperature- dependent and very dynamic, suggesting a direct effect of the temperature on the formation of microtubule/MAP6 complex. We also demonstrate using purified proteins that MAP6-F binds directly to microtubules through its Mc domain. This binding is temperature-dependent and coincides with progressive conformational changes of the Mc domain as revealed by circular dichroism. Thus, MAP6 might serve as a temperature sensor adapting its conformation according to the temperature to maintain the cellular microtubule network in organisms exposed to temperature decrease.

Published
2012
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28. Reduced Expression of STOP/MAP6 in Mice Leads to Cognitive Deficits

Author

Volle, Julien, Brocard, Jacques, Saoud, Mohamed, Gory-Faure, Sylvie, Brunelin, Jérôme, Andrieux, Annie, Suaud-Chagny, Marie-Françoise, Schizophrenies Débutantes et Résistantes : de la Physiopathologie à la Thérapeutique, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, INSERM U836, équipe 1, Physiopathologie du cytosquelette, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier le Vinatier [Bron], Groupe Physiopathologie du Cytosquelette (GPC), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), and Région Rhône-Alpes France ('Cluster 11: Age-Handicap-Vieillissement')

Subjects
behavioural phenotype, neurodevelopment, animal model, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, gene x environment interaction, Schizophrenia, microtubule
Abstract

International audience; Background: STOP/MAP6 null (KO) mice recapitulate behavioral abnormalities related to positive and negative symptoms and cognitive deficits of schizophrenia. Here, we investigated whether decreased expression of STOP/MAP6 proteins in heterozygous mice (only one allele expressed) would result in abnormal behavior related to those displayed by STOP null mice. Methods : Using a comprehensive test battery, we investigated the behavioral phenotype of STOP heterozygous (Het) mice compared with STOP KO and wild type (WT) mice on animals raised either in standard conditions (controls) or submitted to maternal deprivation. Results : Control Het mice displayed prominent deficits in social interaction and learning, resembling KO mice. In contrast, they exhibited short-lasting locomotor hyperreactivity to acute mild stress and no impaired locomotor response to amphetamine, much like WT mice. Additionally, perinatal stress deteriorated Het mouse phenotype by exacerbating alterations related to positive symptoms such as their locomotor reactivity to acute mild stress and psychostimulant challenge. Conclusion : Results show that the dosage of susceptibility genes modulates their putative phenotypic contribution and that STOP expression has a high penetrance on cognitive abilities. Hence, STOP Het mice might be useful to investigate cognitive defects related to those observed in mental diseases and ultimately might be a valuable experimental model to evaluate preventive treatments.

Published
2012
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29. Microtubule-associated STOP protein deletion triggers restricted changes in dopaminergic neurotransmission

Author

Bouvrais-Veret, Caroline, Weiss, Stéphanie, Hanoun, Naima, Andrieux, Annie, Schweitzer, Annie, Job, Didier, Hamon, Michel, Giros, Bruno, Martres, Marie-Pascale, Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropsychopharmacologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Groupe Physiopathologie du Cytosquelette (GPC), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM, Collaboration, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
MESH: Dopamine Uptake Inhibitors, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Mice, Inbred BALB C, cocaine, MESH: Vesicular Monoamine Transport Proteins, MESH: Dopamine, dopaminergic transporter and receptors, MESH: Mice, Knockout, MESH: Dose-Response Relationship, Drug, MESH: Basal Ganglia, MESH: Cocaine, tyrosine hydroxylase, MESH: Analysis of Variance, MESH: Synaptic Transmission, MESH: Receptors, Dopamine, MESH: Animals, MESH: Radiography, MESH: Tyrosine 3-Monooxygenase, MESH: Mice, synaptosomes, cytoskeleton, MESH: Motor Activity, schizophrenia, MESH: Microtubule-Associated Proteins, MESH: Synaptosomes, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Abstract

International audience; The microtubule-associated stable tubule only polypeptide (STOP) protein plays a key-role in neuron architecture and synaptic plasticity. Recent studies suggest that schizophrenia is associated with alterations in the synaptic connectivity. Mice invalidated for the STOP gene display phenotype reminiscent of some schizophrenic-like symptoms, such as behavioral disturbances, dopamine (DA) hyper-reactivity, and possible hypoglutamatergia, partly improved by antipsychotic treatment. In the present work, we examined potential alterations in some DAergic key proteins and behaviors in STOP knockout mice. Whereas the densities of the DA transporter, the vesicular monoamine transporter and the D(1) receptor were not modified, the densities of the D(2) and D(3) receptors were decreased in some DAergic regions in mutant versus wild-type mice. Endogenous DA levels were selectively decreased in DAergic terminals areas, although the in vivo DA synthesis was diminished both in cell bodies and terminal areas. The DA uptake was decreased in accumbic synaptosomes, but not significantly altered in striatal synaptosomes. Finally, STOP knockout mice were hypersensitive to acute and subchronic locomotor effects of cocaine, although the drug equally inhibited DA uptake in mutant and wild-type mice. Altogether, these data showed that deletion of the ubiquitous STOP protein elicited restricted alterations in DAergic neurotransmission, preferentially in the meso-limbic pathway.

Published
2008
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30. Hypoglutamatergic activity in the STOP knockout mouse: a potential model for chronic untreated schizophrenia.: 13C study of metabolism in STOP KO mice

Author

Brenner, Eiliv, Sonnewald, Ursula, Schweitzer, Annie, Andrieux, Annie, Nehlig, Astrid, Department of Neuroscience, Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU)-Norwegian University of Science and Technology (NTNU), Organisation Fonctionnelle du Cytosquelette, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR27, Physiopathologie clinique et expérimentale de la schizophrénie, Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), and Collaboration

Subjects
STOP KO mice, MESH: Neurons, neurons, glutamate, MESH: Dopamine, MESH: Mice, Knockout, MESH: Brain, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Brain Chemistry, MESH: Chromatography, High Pressure Liquid, MESH: Mice, MESH: Glutamine, MESH: Magnetic Resonance Spectroscopy, MESH: Chronic Disease, MESH: Energy Metabolism, astrocytes, MESH: Glutamic Acid, MESH: Synaptic Vesicles, MESH: Male, MESH: Schizophrenia, schizophrenia, MESH: Astrocytes, MESH: Microtubule-Associated Proteins, glutamine, MESH: Disease Models, Animal
Abstract

International audience; In mice, the deletion of the STOP protein leads to hyperdopaminergia and major behavioral disorders that are alleviated by neuroleptics, representing a potential model of schizophrenia. The reduction of the glutamatergic synaptic vesicle pool in the hippocampus could reflect a disturbance in glutamatergic neurotransmission in this model. Here we examined potential disturbances in energy metabolism and interactions between neurons and glia in 15-week-old STOP KO, wild-type, and heterozygous mice. Animals received [1-(13)C]glucose and [1,2-(13)C]acetate, the preferential substrates of neurons and astrocytes, respectively. Extracts from the whole forebrain and midbrain were analyzed by HPLC, (13)C and (1)H NMR spectroscopy. Amounts and labeling of most metabolites were unchanged. However, glutamine concentration and amount of [4,5-(13)C]glutamine derived from [1,2-(13)C]acetate significantly decreased by 17% and 18%, respectively, in STOP KO compared with wild-type mice. The amount of [4-(13)C]glutamate was decreased in STOP KO and heterozygous compared with wild-type mice. gamma-Aminobutyric acid labeling was not influenced by the genotype. Because STOP-deficient mice have a lower synaptic vesicle density, less glutamate is released to the synaptic cleft, leading to decreased stimulation of the postsynaptic glutamate receptors, reflecting increased glutamine metabolism only in the vicinity of the postsynapse of STOP KO mice.

Published
2007
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31. Phosphorylation of microtubule-associated protein STOP by calmodulin kinase II

Author

Baratier, Julie, Peris, Leticia, Brocard, Jacques, Gory-Fauré, Sylvie, Dufour, Fabrice, Bosc, Christophe, Fourest-Lieuvin, Anne, Blanchoin, Laurent, Salin, Paul, Job, Didier, Andrieux, Annie, Organisation Fonctionnelle du Cytosquelette, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR27, Laboratoire de physiologie cellulaire végétale (LPCV), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Physio-pathologie des réseaux neuronaux du cycle veille-sommeil, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), This work was supported in part by grants from La Ligue Nationale contre le Cancer to D.J., Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
MESH: Protein Transport, MESH: Hippocampus, MESH: Neurons, MESH: Microscopy, Fluorescence, Actins, Animals, Brain, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calcium-Calmodulin-Dependent Protein Kinases, Calmodulin, Hippocampus, Mice, Microscopy, Fluorescence, Microtubule-Associated Proteins, Microtubules, Neurons, Phosphorylation, Protein Transport, Synapses, MESH: Actins, MESH: Synapses, MESH: Brain, SDV:BBM, MESH: Calcium-Calmodulin-Dependent Protein Kinases, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, MESH: Phosphorylation, MESH: Microtubules, MESH: Calmodulin, MESH: Microtubule-Associated Proteins, MESH: Calcium-Calmodulin-Dependent Protein Kinase Type 2
Abstract

International audience; STOP proteins are microtubule-associated, calmodulin-regulated proteins responsible for the high degree of stabilization displayed by neuronal microtubules. STOP suppression in mice induces synaptic defects affecting both short and long term synaptic plasticity in hippocampal neurons. Interestingly, STOP has been identified as a component of synaptic structures in neurons, despite the absence of microtubules in nerve terminals, indicating the existence of mechanisms able to induce a translocation of STOP from microtubules to synaptic compartments. Here we have tested STOP phosphorylation as a candidate mechanism for STOP relocalization. We show that, both in vitro and in vivo, STOP is phosphorylated by the multifunctional enzyme calcium/calmodulin-dependent protein kinase II (CaMKII), which is a key enzyme for synaptic plasticity. This phosphorylation occurs on at least two independent sites. Phosphorylated forms of STOP do not bind microtubules in vitro and do not co-localize with microtubules in cultured differentiating neurons. Instead, phosphorylated STOP co-localizes with actin assemblies along neurites or at branching points. Correlatively, we find that STOP binds to actin in vitro. Finally, in differentiated neurons, phosphorylated STOP co-localizes with clusters of synaptic proteins, whereas unphosphorylated STOP does not. Thus, STOP phosphorylation by CaMKII may promote STOP translocation from microtubules to synaptic compartments where it may interact with actin, which could be important for STOP function in synaptic plasticity.

Published
2006
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32. Revival of ancient marine dinoflagellates using molecular biostimulation

Author

Axel Ehrhold, Marie Latimier, Sabine Schmidt, Gaspard Delebecq, Raffaele Siano, Laboratoire des Sciences de l'Environnement Marin (LEMAR) (LEMAR), Institut de Recherche pour le Développement (IRD)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Brest (UBO)-Institut Universitaire Européen de la Mer (IUEM), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), UMR 5805 Environnements et Paléoenvironnements Océaniques et Continentaux (EPOC), Observatoire aquitain des sciences de l'univers (OASU), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-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)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche Géosciences Marines (Ifremer) (GM), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), Dynamiques de l'Environnement Côtier (DYNECO), and Research funds were provided by the Brittany Region as part of the project PALMIRA (Paleoecology of Alexandrium minutum dans la Rade de Brest-Marche n degrees 2017-90292) which supported the core sampling, analyses, and post-doc fellowship of GD. We thank Arnaud Marrec and Yannick Fagon (Region Bretagne -Service Ing~enierie de la Direction des Ports), who allowed the implementation and progression of the project PALMIRA. We are grateful to all members of the crew of the N/O Thalia ship of Ifremer for providing technical expertise in sediment core collection. We thank Angelique Roubi and Jeremie Gouriou of the laboratory GM/LGS of Ifremer for helping during core sampling onboard. The colleagues of the laboratory DYNECO/Pelagos and LER/BO of Ifremer (Francoise Andrieux, Annie Chapelle, Cecile Jauzein, Mickael Le Gac, Kenneth Mertens, Martin Plus, Sophie Schmitt, Agnes Youenou) are acknowledged for their assistance during core subsampling. We thank Julien Quere of DYNECO/Pelagos for the molecular identification of revived strains, Michel Le Duff of the UMS 3113 for taxonomic identification of gastropod shells used for radiocarbon dating, and Nicolas Chom~erat and Kenneth Mertens for their help with taxonomic identification of dinoflagellates. We also thank Amelia Curd for English editing of the manuscript. We are grateful to Malwenn Lassudrie of the laboratory LER/BO for her contribution to the project. St~ephane Lesbats and Olivier Dugornay of Ifremer's Audiovisual Service are thanked for collecting onboard and scuba diving images of the sampling and for producing videos for the project. We certify that there is no conflict of interest with any financial organization regarding the material discussed in this manuscript.

Subjects
0106 biological sciences, Alexandrium minutum, acl, [SDE.MCG]Environmental Sciences/Global Changes, Alexandrium, melatonin, Plant Science, Aquatic Science, dinoflagellate, 010603 evolutionary biology, 01 natural sciences, paleoecology, Melatonin, Biostimulation, chemistry.chemical_compound, Botany, medicine, High doses, 14. Life underwater, resurrection ecology, priming, Gibberellic acid, cyst, Resurrection ecology, biology, 010604 marine biology & hydrobiology, Dinoflagellate, Bay of Brest, biology.organism_classification, revival, chemistry, sediment, Germination, Scrippsiella, Dinoflagellida, France, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, gibberellic acid, medicine.drug
Abstract

International audience; The biological processes involved in the preservation, viability, and revival of long‐term dormant dinoflagellate cysts buried in sediments remain unknown. Based on studies of plant seed physiology, we tested whether the revival of ancient cysts preserved in century‐old sediments from the Bay of Brest (France) could be stimulated by melatonin and gibberellic acid, two molecules commonly used in seed priming. Dinoflagellates were revived from sediments dated to approximately 150 years ago (156 ± 27, 32 cm depth), extending the known record age of cyst viability previously established as around one century. A culture suspension of sediments mixed with melatonin and gibberellic acid solutions as biostimulants exhibited germination of 11 dinoflagellate taxa that could not be revived under controlled culture conditions. The biostimulants revived some dinoflagellates from century‐old sediments, including the potentially toxic species Alexandrium minutum. The biostimulants showed positive effects on germination on even more ancient cysts, showing dose‐dependent effects on the germination of Scrippsiella acuminata. Concentrations of 1, 10, and 100 µM melatonin and gibberellic acid promoted germination. In contrast, 1000 µM solutions, particularly for melatonin, drastically decreased germination, suggesting a potential noxious effect of high doses of these molecules on dinoflagellate revival. Our findings suggest that melatonin and gibberellic acid are involved in the stimulation of germination of dinoflagellate cysts. These biostimulants can be used to germinate long‐term stored dinoflagellate cysts, which may promote studies of ancient strains in the resurrection ecology research field.

Published
2020
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33. The cytosolic carboxypeptidases CCP2 and CCP3 catalyze posttranslational removal of acidic amino acids

Author

Sebastian Tanco, Julia Lorenzo, Ivan Bièche, Christophe Bosc, Cecilia Rocha, Francesc X. Avilés, Carsten Janke, Annie Andrieux, Marie-Jo Moutin, Cecília Seixas, Olivia Tort, Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona (UAB), Institut Curie [Paris], Department of Biochemistry, Universiteit Gent = Ghent University [Belgium] (UGENT), Department of Medical Protein Research (VIB), Signalisation, neurobiologie et cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL), INSERM U836, équipe 1, Physiopathologie du cytosquelette, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School - Faculdade de Ciências Médicas (NMS), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Physiopathologie du Cytosquelette, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), This work was supported by Spanish Ministry of Science and Innovation Grant BIO2013-44973-R, the Network of Excellence of the Generalitat de Catalunya (SGR, Spain), a Predoctoral Contract for Training in Health Research (PFIS) grant from Instituto Carlos III, an EMBO short-term fellowship (ASTF 45-2014), the Institut Curie, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, and Fondation Pierre-Gilles de Gennes 3T grant (C.J.), FRM Grant FDT20120925331 (C.R.), a Fundação para a Ciência e a Tecnologia postdoctoral grant (A.C.S.), French National Research Agency (ANR) Awards ANR-12-BSV2-0007, ANR-10-LBX-0038, and part of ANR-10-IDEX-0001-02 PSL (C.J.), INCA Grant 2009-1-PLBIO-12-IC (C.J.), ARC Program SL220120605303 (C.J.), the EMBO Young Investigators Programme (C.J.), Project Tyr-TIPs-ANR-07-BLAN-0045 (A.A.), ARC Grant SFI20111204053 (M.J.M.), and a grant of La Ligue contre le Cancer comité de Savoie (M.J.M.)., Universiteit Gent = Ghent University (UGENT), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Andrieux, Annie, and NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)

Subjects
Protein family, Cytosolic carboxypeptidases, Glutamic Acid, macromolecular substances, Carboxypeptidases, Microtubules, Granzymes, Cell Line, Substrate Specificity, 03 medical and health sciences, Mice, 0302 clinical medicine, Microtubule, Catalytic Domain, Animals, Humans, Amino Acid Sequence, Cilia, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Molecular Biology, Peptide sequence, Cytoskeleton, 030304 developmental biology, chemistry.chemical_classification, Mice, Knockout, 0303 health sciences, Aspartic Acid, biology, Cell Biology, Articles, Actin cytoskeleton, Carboxypeptidase, Cell biology, Cytosol, Actin Cytoskeleton, Tubulin, Enzyme, HEK293 Cells, chemistry, Biochemistry, biology.protein, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], CCP2, CCP3, Protein Processing, Post-Translational, 030217 neurology & neurosurgery
Abstract

The posttranslational modification of tubulin plays an important role in regulating microtubule function. Enzymes responsible for deglutamylating tubulin are members of a family of cytosolic carboxypeptidases. By completing the functional characterization of this protein family in mammals, it is demonstrated that CCP2 and CCP3 are deglutamylases., The posttranslational modification of carboxy-terminal tails of tubulin plays an important role in the regulation of the microtubule cytoskeleton. Enzymes responsible for deglutamylating tubulin have been discovered within a novel family of mammalian cytosolic carboxypeptidases. The discovery of these enzymes also revealed the existence of a range of other substrates that are enzymatically deglutamylated. Only four of six mammalian cytosolic carboxypeptidases had been enzymatically characterized. Here we complete the functional characterization of this protein family by demonstrating that CCP2 and CCP3 are deglutamylases, with CCP3 being able to hydrolyze aspartic acids with similar efficiency. Deaspartylation is a novel posttranslational modification that could, in conjunction with deglutamylation, broaden the range of potential substrates that undergo carboxy-terminal processing. In addition, we show that CCP2 and CCP3 are highly regulated proteins confined to ciliated tissues. The characterization of two novel enzymes for carboxy-terminal protein modification provides novel insights into the broadness of this barely studied process.

Published
2014
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34. Neuronal transport defects of the MAP6 KO mouse - a model of schizophrenia - and alleviation by Epothilone D treatment, as observed using MEMRI

Author

Sylvain Bohic, Annie Andrieux, Yasmina Saoudi, Emmanuel L. Barbier, Alexia Daoust, Jean-Christophe Deloulme, Clément Debacker, Sylvie Gory-Fauré, INSERM U836, équipe 6, Rayonnement synchrotron et recherche médicale, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), European Synchrotron Radiation Facility (ESRF)-Grenoble Institut des Neurosciences (GIN), INSERM U836, équipe 1, Physiopathologie du cytosquelette, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), INSERM U836, équipe 5, Neuroimagerie fonctionnelle et perfusion cérébrale, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Bruker Biospin MRI, Bruker Biospin MRI-Bruker Biospin MRI, ANR-10-BLAN-1202,CBioS,Fonctions cellulaires des protéines STOP : vers une compréhension fonctionnelle et moléculaire du rôle des microtubules dans la transmission synaptique et l'organisation neuronale(2010), European Project, Andrieux, Annie, BLANC - Fonctions cellulaires des protéines STOP : vers une compréhension fonctionnelle et moléculaire du rôle des microtubules dans la transmission synaptique et l'organisation neuronale - - CBioS2010 - ANR-10-BLAN-1202 - BLANC - VALID, Région Rhône-Alpes - Cluster HVN, and INCOMING

Subjects
medicine.medical_specialty, Cognitive Neuroscience, Contrast Media, MEMRI, Neurotransmission, Somatosensory system, Synaptic Transmission, 03 medical and health sciences, Mice, 0302 clinical medicine, In vivo, Internal medicine, medicine, Animals, Humans, MAP6, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuronal transport, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Manganese, medicine.diagnostic_test, Chemistry, Magnetic resonance imaging, Somatosensory Cortex, Magnetic Resonance Imaging, Tubulin Modulators, 3. Good health, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, Treatment Outcome, Neurology, Epothilones, Synaptic plasticity, Axoplasmic transport, Schizophrenia, Epothilone D, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, Microtubule-Associated Proteins, 030217 neurology & neurosurgery, Neuronal tract
Abstract

International audience; The MAP6 (microtubule-associated protein 6) KO mouse is a microtubule-deficient model of schizophrenia that exhibits severe behavioral disorders that are associated with synaptic plasticity anomalies. These defects are alleviated not only by neuroleptics, which are the gold standard molecules for the treatment of schizophrenia, but also by Epothilone D (Epo D), which is a microtubule-stabilizing molecule. To compare the neuronal transport between MAP6 KO and wild-type mice and to measure the effect of Epo D treatment on neuronal transport in KO mice, MnCl2 was injected in the primary somatosensory cortex. Then, using manganese-enhanced magnetic resonance imaging (MEMRI), we followed the propagation of Mn(2+) through axonal tracts and brain regions that are connected to the somatosensory cortex. In MAP6 KO mice, the measure of the MRI relative signal intensity over 24h revealed that the Mn(2+) transport rate was affected with a stronger effect on long-range and polysynaptic connections than in short-range and monosynaptic tracts. The chronic treatment of MAP6 KO mice with Epo D strongly increased Mn(2+) propagation within both mono- and polysynaptic connections. Our results clearly indicate an in vivo deficit in neuronal Mn(2+) transport in KO MAP6 mice, which might be due to both axonal transport defects and synaptic transmission impairments. Epo D treatment alleviated the axonal transport defects, and this improvement most likely contributes to the positive effect of Epo D on behavioral defects in KO MAP6 mice.

Published
2014
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35. Microtubule-targeting drugs rescue axonal swellings in cortical neurons from spastin knockout mice: Microtubule dynamics and spastin mutant mice

Author

Fassier, Coralie, Couturier-Tarrade, Anne, Peris, Leticia, Courageot, Sabrina, Mailly, Philippe, Dalard, Cécile, Delga, Stéphanie, Roblot, Natacha, Lefèvre, Julien, Job, Didier, Hazan, Jamilé, Curmi, Patrick, Melki, Judith, Andrieux, Annie, Neurogenetique Moleculaire, Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie des Maladies du Système Nerveux Central, 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), Structure et activité des biomolécules normales et pathologiques (SABNP), INSERM U836, équipe 1, Physiopathologie du cytosquelette, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), and INSERM Fédération pour la Recherche sur le Cerveau GISANR Maladies Rares Université d'Evry Conseil Régional d'Ile de France

Subjects
knock-out mouse model, nervous system, microtubule-severing enzyme, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, spastin, hereditary spastic paraplegia, axonal transport, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, microtubule-targeting drugs
Abstract

International audience; Mutations in SPG4, encoding the microtubule-severing protein spastin, are responsible for the most frequent form of hereditary spastic paraplegia (HSP), a heterogeneous group of genetic diseases characterized by degeneration of the corticospinal tracts. We previously reported that mice harboring a deletion in Spg4, generating a premature stop codon, develop progressive axonal degeneration characterized by focal axonal swellings associated with impaired axonal transport. To further characterize the molecular and cellular mechanisms underlying this mutant phenotype, we have assessed microtubule dynamics and axonal transport in primary cultures of cortical neurons from spastin-mutant mice. We show an early and marked impairment of microtubule dynamics all along the axons of spastin-deficient cortical neurons, which is likely to be responsible for the occurrence of axonal swellings and cargo stalling. Our analysis also reveals that a modulation of microtubule dynamics by microtubule-targeting drugs rescues the mutant phenotype of cortical neurons. Together, these results contribute to a better understanding of the pathogenesis of SPG4-linked HSP and ascertain the influence of microtubule-targeted drugs on the early axonal phenotype in a mouse model of the disease.

Published
2013
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36. A novel mass assay to quantify the bioactive lipid PtdIns3P in various biological samples

Author

Cécile Boscheron, Sonia Severin, Anne-Dominique Terrisse, Gaëtan Chicanne, Frédérique Gaits-Iacovoni, Marie-Pierre Gratacap, Bernard Payrastre, Hélène Tronchère, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U836, équipe 1, Physiopathologie du cytosquelette, Groupe Physiopathologie du Cytosquelette (GPC), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire d'Hématologie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], E-Rare Inserm Transfert Région Midi-Pyrénées ANR Grant 07-BLAN-0065, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Grenoble Institut des Neurosciences (GIN), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Andrieux, Annie

Subjects
Biochemistry, High-performance liquid chromatography, Mass Spectrometry, PX, Phox homology, Substrate Specificity, PIKFYVE, chemistry.chemical_compound, Mice, Phosphatidylinositol 3-Kinases, class III phosphoinositide 3-kinase, 0302 clinical medicine, Phosphatidylinositol Phosphates, Cricetinae, GST, glutathione transferase, GFP, green fluorescent protein, 0303 health sciences, PtdIns3P, 3. Good health, Midbody, 030220 oncology & carcinogenesis, TRAP, thrombin-receptor-agonist peptide, PI3K, phosphoinositide 3-kinase, Research Article, Blood Platelets, Saccharomyces cerevisiae Proteins, Endosome, PtdInsP2, phosphatidylinositol diphosphate, Recombinant Fusion Proteins, MTMR, MTM-related, Endosomes, Saccharomyces cerevisiae, Biology, PE, phosphatidylethanolamine, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MTM, myotubularin, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Phosphatidylinositol, Molecular Biology, 030304 developmental biology, Autophagy, Cell Biology, PtdInsP, phosphatidylinositol monophosphate, PIKfyve, Class III Phosphatidylinositol 3-Kinases, chemistry, EEA1, early endosome antigen 1, mass assay, Cytokinesis, Chromatography, Liquid
Abstract

International audience; PtdIns3P is recognized as an important player in the control of the endocytotic pathway and in autophagy. Recent data also suggest that PtdIns3P contributes to molecular mechanisms taking place at the plasma membrane and at the midbody during cytokinesis. This lipid is present in low amounts in mammalian cells and remains difficult to quantify either by traditional techniques based on radiolabelling followed by HPLC to separate the different phosphatidylinositol monophosphates, or by high-sensitive liquid chromatography coupled to MS, which is still under development. In the present study, we describe a mass assay to quantify this lipid from various biological samples using the recombinant PtdIns3P 5-kinase, PIKfyve. Using this assay, we show an increase in the mass level of PtdIns3P in mouse and human platelets following stimulation, loss of this lipid in Vps34-deficient yeasts and its relative enrichment in early endosomes isolated from BHK cells.

Published
2012
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37. The antidepressant hyperforin increases the phosphorylation of CREB and the expression of TrkB in a tissue-specific manner

Author

Tiphaine Chevallier, Jean-Christophe Deloulme, Djoher Nora Abrous, Alexandre Bouron, E. Ladevèze, Julien Gibon, Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), INSERM U836, équipe 1, Physiopathologie du cytosquelette, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie du système nerveux central - Institut François Magendie, Université Bordeaux Segalen - Bordeaux 2-IFR8-Institut National de la Santé et de la Recherche Médicale (INSERM), MENRT, Région Rhône-Alpes (Cluster 11, 'Handicap, Vieillissement, Neurosciences'), INSERM, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Andrieux, Annie

Subjects
Male, TRPC6, Tropomyosin receptor kinase B, Pharmacology, Hippocampal formation, Hippocampus, chemistry.chemical_compound, Mice, 0302 clinical medicine, Pregnancy, Pharmacology (medical), Tissue Distribution, PKA, Phosphorylation, Cyclic AMP Response Element-Binding Protein, Cells, Cultured, Cerebral Cortex, Neurons, 0303 health sciences, biology, CREB, Neurogenesis, Age Factors, TrkB, Hypericum perforatum, Antidepressants, Antidepressive Agents, Up-Regulation, Psychiatry and Mental health, neurogenesis, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Phloroglucinol, 03 medical and health sciences, Animals, Receptor, trkB, Cyclic adenosine monophosphate, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, Terpenes, Mice, Inbred C57BL, Hyperforin, chemistry, nervous system, biology.protein, 030217 neurology & neurosurgery
Abstract

Hyperforin is one of the main bioactive compounds that underlie the antidepressant actions of the medicinal plant Hypericum perforatum (St. John's wort). However, the effects of a chronic hyperforin treatment on brain cells remains to be fully addressed. The following study was undertaken to further advance our understanding of the biological effects of this plant extract on neurons. Special attention was given to its impact on the brain-derived neurotrophic factor (BDNF) receptor TrkB and on adult hippocampal neurogenesis since they appear central to the mechanisms of action of antidepressants. The consequences of a chronic hyperforin treatment were investigated on cortical neurons in culture and on the brain of adult mice treated for 4 wk with a daily injection (i.p.) of hyperforin (4 mg/kg). Its effects on the expression of the cyclic adenosine monophosphate response element-binding protein (CREB), phospho-CREB (p-CREB), TrkB and phospho-TrkB (p-TrkB) were analysed by Western blot experiments and its impact on adult hippocampal neurogenesis was also investigated. Hyperforin stimulated the expression of TRPC6 channels and TrkB via SKF-96365-sensitive channels controlling a downstream signalling cascade involving Ca2+, protein kinase A, CREB and p-CREB. In vivo, hyperforin augmented the expression of TrkB in the cortex but not in the hippocampus where hippocampal neurogenesis remained unchanged. In conclusion, this plant extract acts on the cortical BDNF/TrkB pathway leaving adult hippocampal neurogenesis unaffected. This study provides new insights on the neuronal responses controlled by hyperforin. We propose that the cortex is an important brain structure targeted by hyperforin.

Published
2012
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38. Bmcc1s, a novel brain-isoform of Bmcc1, affects cell morphology by regulating MAP6/STOP functions

Author

Edwige Amigou, Christian Delphin, Christophe Bosc, Laure Wingertsmann, Jessica Arama, Martine Cohen-Salmon, Anne-Cécile Boulay, Laurent Guillaud, Philippe Rostaing, Damarys Loew, Christian Giaume, Annie Andrieux, Pascal Ezan, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-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), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution)), INSERM U836, équipe 1, Physiopathologie du cytosquelette, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Spectrométrie de Masse Protéomique, Institut Curie [Paris], Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cell and Molecular Synaptic Function Unit, Okinawa Institute of Science and Technology Graduate University (OIST), Groupe Physiopathologie du Cytosquelette (GPC), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), cancéropole Institut National du Cancer, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL), Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut 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)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Grenoble Institut des Neurosciences (GIN), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), and Andrieux, Annie

Subjects
Central Nervous System, Anatomy and Physiology, Mouse, MESH: Cold Temperature, MESH: Neurons, lcsh:Medicine, Gene Expression, MESH: Amino Acid Sequence, MESH: Protein Isoforms, Cell morphology, Microtubules, Mice, 0302 clinical medicine, Molecular Cell Biology, Protein Isoforms, MESH: Animals, MAP6, MESH: Nerve Tissue Proteins, Cytoskeleton, Intermediate filament, lcsh:Science, ComputingMilieux_MISCELLANEOUS, Neurons, 0303 health sciences, Multidisciplinary, MESH: Microtubules, Brain, Animal Models, Cellular Structures, Cell biology, Neoplasm Proteins, Cold Temperature, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cellular Types, Microtubule-Associated Proteins, Research Article, Gene isoform, Neurite, Microtubule-associated protein, Molecular Sequence Data, Nerve Tissue Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Neurological System, Molecular Genetics, 03 medical and health sciences, MESH: Brain, Model Organisms, Microtubule, Genetics, Animals, Humans, Gene Regulation, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Amino Acid Sequence, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, 030304 developmental biology, MESH: Molecular Sequence Data, MESH: Humans, lcsh:R, MESH: Astrocytes, MESH: Microtubule-Associated Proteins, Astrocytes, MESH: HeLa Cells, Nervous System Components, lcsh:Q, 030217 neurology & neurosurgery, HeLa Cells
Abstract

The BCH (BNIP2 and Cdc42GAP Homology) domain-containing protein Bmcc1/Prune2 is highly enriched in the brain and is involved in the regulation of cytoskeleton dynamics and cell survival. However, the molecular mechanisms accounting for these functions are poorly defined. Here, we have identified Bmcc1s, a novel isoform of Bmcc1 predominantly expressed in the mouse brain. In primary cultures of astrocytes and neurons, Bmcc1s localized on intermediate filaments and microtubules and interacted directly with MAP6/STOP, a microtubule-binding protein responsible for microtubule cold stability. Bmcc1s overexpression inhibited MAP6-induced microtubule cold stability by displacing MAP6 away from microtubules. It also resulted in the formation of membrane protrusions for which MAP6 was a necessary cofactor of Bmcc1s. This study identifies Bmcc1s as a new MAP6 interacting protein able to modulate MAP6-induced microtubule cold stability. Moreover, it illustrates a novel mechanism by which Bmcc1 regulates cell morphology.

Published
2012
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39. How morphological constraints affect axonal polarity in mouse neurons

Author

Sophie Roth, Catherine Villard, Sylvie Gory-Fauré, Mariano Bisbal, Yasmina Saoudi, Annie Andrieux, Ghislain Bugnicourt, Jacques Brocard, INSERM U836, équipe 1, Physiopathologie du cytosquelette, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Néel (NEEL), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Physiopathologie du Cytosquelette (GPC), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut Néel (NEEL), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), Thermodynamique et biophysique des petits systèmes (TPS), Institut Néel (NEEL), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Nanoscience Foundation, Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Grenoble Institut des Neurosciences (GIN), Thermodynamique et biophysique des petits systèmes (NEEL - TPS), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS), and Andrieux, Annie

Subjects
MESH: Hippocampus, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cell, MESH: Neurons, lcsh:Medicine, Hippocampal formation, Hippocampus, MESH: Centrosome, Mice, chemistry.chemical_compound, 0302 clinical medicine, Cell polarity, Biomechanics, Cytochalasin, MESH: Animals, Axon, lcsh:Science, Cells, Cultured, Neurons, 0303 health sciences, Multidisciplinary, [PHYS.PHYS.PHYS-BIO-PH] Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Physics, Cell Polarity, Anatomy, Cell Motility, medicine.anatomical_structure, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Cell Polarity, Research Article, Biotechnology, MESH: Cells, Cultured, MESH: Axons, Neurite, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Biophysics, Biology, 03 medical and health sciences, Developmental Neuroscience, Microtubule, medicine, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Mice, 030304 developmental biology, Centrosome, lcsh:R, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Axons, chemistry, nervous system, Cellular Neuroscience, lcsh:Q, Neuroscience, 030217 neurology & neurosurgery
Abstract

International audience; Neuronal differentiation is under the tight control of both biochemical and physical information arising from neighboring cells and micro-environment. Here we wished to assay how external geometrical constraints applied to the cell body and/or the neurites of hippocampal neurons may modulate axonal polarization in vitro. Through the use of a panel of non-specific poly-L-lysine micropatterns, we manipulated the neuronal shape. By applying geometrical constraints on the cell body we provided evidence that centrosome location was not predictive of axonal polarization but rather follows axonal fate. When the geometrical constraints were applied to the neurites trajectories we demonstrated that axonal specification was inhibited by curved lines. Altogether these results indicated that intrinsic mechanical tensions occur during neuritic growth and that maximal tension was developed by the axon and expressed on straight trajectories. The strong inhibitory effect of curved lines on axon specification was further demonstrated by their ability to prevent formation of multiple axons normally induced by cytochalasin or taxol treatments. Finally we provided evidence that microtubules were involved in the tension-mediated axonal polarization, acting as curvature sensors during neuronal differentiation. Thus, biomechanics coupled to physical constraints might be the first level of regulation during neuronal development, primary to biochemical and guidance regulations.

Published
2012
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40. Cap-Gly proteins at microtubule plus ends: is EB1 detyrosination involved?

Author

Marie-Jo Moutin, Didier Job, Anouk Bosson, Annie Andrieux, Odile Valiron, Jean-Marc Soleilhac, INSERM U836, équipe 1, Physiopathologie du cytosquelette, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Physiopathologie du Cytosquelette (GPC), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), ARC (4892 et 7927), Andrieux, Annie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Grenoble Institut des Neurosciences (GIN)

Subjects
lcsh:Medicine, MESH: Tubulin, Microtubules, Biochemistry, MESH: Tyrosine, MESH: Recombinant Proteins, Mice, MESH: Protein Structure, Tertiary, Antibody Specificity, Tubulin, Molecular Cell Biology, MESH: Animals, Tyrosine, lcsh:Science, chemistry.chemical_classification, 0303 health sciences, Multidisciplinary, biology, MESH: Microtubules, 030302 biochemistry & molecular biology, Brain, Recombinant Proteins, Cellular Structures, Amino acid, Cell biology, Cell Motility, MESH: Cattle, Microtubule-Associated Proteins, Research Article, Microtubule-associated protein, Biophysics, macromolecular substances, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Cleavage (embryo), Antibodies, 03 medical and health sciences, MESH: Brain, Microtubule, Detyrosination, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Antibody Specificity, Biology, MESH: Mice, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, MESH: Antibodies, lcsh:R, fungi, Proteins, Fibroblasts, Carboxypeptidase, Protein Structure, Tertiary, MESH: Microtubule-Associated Proteins, chemistry, MESH: Fibroblasts, biology.protein, lcsh:Q, Cattle
Abstract

International audience; Localization of CAP-Gly proteins such as CLIP170 at microtubule+ends results from their dual interaction with α-tubulin and EB1 through their C-terminal amino acids -EEY. Detyrosination (cleavage of the terminal tyrosine) of α-tubulin by tubulin-carboxypeptidase abolishes CLIP170 binding. Can detyrosination affect EB1 and thus regulate the presence of CLIP170 at microtubule+ends as well? We developed specific antibodies to discriminate tyrosinated vs detyrosinated forms of EB1 and detected only tyrosinated EB1 in fibroblasts, astrocytes, and total brain tissue. Over-expressed EB1 was not detyrosinated in cells and chimeric EB1 with the eight C-terminal amino acids of α-tubulin was only barely detyrosinated. Our results indicate that detyrosination regulates CLIPs interaction with α-tubulin, but not with EB1. They highlight the specificity of carboxypeptidase toward tubulin.

Published
2012
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41. Mapping of endogenous morphine-like compounds in the adult mouse brain: Evidence of their localization in astrocytes and GABAergic cells

Author

Denise Stuber, Yannick Goumon, Jean-Christophe Deloulme, Dominique Sage, Sylvie Dirrig-Grosch, François Delalande, Alexis Laux, Dominique Aunis, Arnaud Muller, Pierrick Poisbeau, Monique Miehe, Alain Van Dorsselaer, Physiopathologie du système nerveux., Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), Département Neurotransmission et sécrétion neuroendocrine, Centre National de la Recherche Scientifique (CNRS), Plateforme imagerie cellulaire Strasbourg esplanade (Plateforme d'imagerie in vitro), Laboratoire de signalisation moléculaire et neurodégénerescence, INSERM U836, équipe 1, Physiopathologie du cytosquelette, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] (LSMBO), Département 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), Plateforme d'hébergement et d'exploration fonctionnelle (Chronobiotron), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), INSERM CNRS Université de Strasbourg Ministère Français délégué à la Recherche et à l'Enseignement supérieur Fondation Transplantation Fondation pour la recherche médicale, Institut des Neurosciences Cellulaires et Intégratives (INCI), and Andrieux, Annie

Subjects
Male, Cerebellum, Patch-Clamp Techniques, Dopamine, MESH: Neurons, Hippocampus, Endogeny, MESH: gamma-Aminobutyric Acid, Mice, 0302 clinical medicine, Postsynaptic potential, MESH: Animals, MESH: Brain Chemistry, gamma-Aminobutyric Acid, Neurons, 0303 health sciences, Morphine, General Neuroscience, Brain, Immunohistochemistry, 3. Good health, medicine.anatomical_structure, MESH: Morphine Derivatives, GABAergic, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.drug, Cell type, MESH: Dopamine, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH: Codeine, 03 medical and health sciences, MESH: Brain, MESH: Mice, Inbred C57BL, MESH: Patch-Clamp Techniques, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, 030304 developmental biology, Brain Chemistry, Morphine Derivatives, MESH: Humans, Codeine, MESH: Immunohistochemistry, Morphine-6-glucuronide, MESH: Male, Olfactory bulb, Mice, Inbred C57BL, MESH: Astrocytes, MESH: Morphine, Astrocytes, Neuroscience, 030217 neurology & neurosurgery
Abstract

Endogenous morphine, morphine-6-glucuronide, and codeine, which are structurally identical to vegetal alkaloids, can be synthesized by mammalian cells from dopamine. However, the role of brain endogenous morphine and its derivative compounds is a matter of debate, and knowledge about its distribution is lacking. In this study, by using a validated antibody, we describe a precise mapping of endogenous morphine-like compounds (morphine and/or its glucuronides and/or codeine) in the mouse brain. First, a mass spectrometry approach confirmed the presence of morphine and codeine in mouse brain, but also, of morphine-6-glucuronide and morphine-3-glucuronide representing two metabolites of morphine. Second, light microscopy allowed us to observe immunopositive cell somas and cytoplasmic processes throughout the mouse brain. Morphine-like immunoreactivity was present in various structures including the hippocampus, olfactory bulb, band of Broca, basal ganglia, and cerebellum. Third, by using confocal microscopy and immunofluroscence co-localization, we characterized cell types containing endogenous opiates. Interestingly, we observed that morphine-like immunoreactivity throughout the encephalon is mainly present in γ-aminobutyric acid (GABA)ergic neurons. Astrocytes were also labeled throughout the entire brain, in the cell body, in the cytoplasmic processes, and in astrocytic feet surrounding blood vessels. Finally, ultrastructural localization of morphine-like immunoreactivity was determined by electron microscopy and showed the presence of morphine-like label in presynaptic terminals in the cerebellum and postsynaptic terminals in the rest of the mouse brain. In conclusion, the presence of endogenous morphine-like compounds in brain regions not usually involved in pain modulation opens the exciting opportunity to extend the role and function of endogenous alkaloids far beyond their analgesic functions. J. Comp. Neurol. 519:2390–2416, 2011. © 2011 Wiley-Liss, Inc.

Published
2011
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42. Regulatory modules function in a non-autonomous manner to control transcription of the mbp gene

Author

Nancy Dionne, Hana H. Friedman, Eric Denarier, Mélissa Beaudoin, Alan C. Peterson, Samar Dib, Department of Human Genetics [Montréal], McGill University = Université McGill [Montréal, Canada], ANTE-INSERM U836, équipe 1, Physiopathologie du cytosquelette, McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Canadian Institutes of health Research, Multiple Sclerosis Society of Canada, CEA, Genome Quebec and Genome Canada, and Andrieux, Annie

Subjects
Transcription factories, Transcription, Genetic, MESH: Myelin Sheath, Interactome, MESH: Mice, Knockout, Mice, 0302 clinical medicine, MESH: Animals, MESH: Gene Silencing, Promoter Regions, Genetic, Myelin Sheath, Genetics, Mice, Knockout, 0303 health sciences, MESH: Oligodendroglia, MESH: Transcription Factors, Oligodendroglia, Enhancer Elements, Genetic, Regulatory sequence, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Mice, Transgenic, Mice, Transgenic, Computational biology, Biology, Gene Regulation, Chromatin and Epigenetics, MESH: Genetic Loci, 03 medical and health sciences, MESH: Promoter Regions, Genetic, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Gene Silencing, Enhancer, Gene, Transcription factor, MESH: Mice, 030304 developmental biology, MESH: Myelin Basic Proteins, Reporter gene, MESH: Transcription, Genetic, Promoter, Myelin Basic Protein, Genetic Loci, Schwann Cells, MESH: Enhancer Elements, Genetic, MESH: Schwann Cells, 030217 neurology & neurosurgery, Transcription Factors
Abstract

International audience; Multiple regulatory modules contribute to the complex expression programs realized by many loci. Although long thought of as isolated components, recent studies demonstrate that such regulatory sequences can physically associate with promoters and with each other and may localize to specific sub-nuclear transcription factories. These associations provide a substrate for putative interactions and have led to the suggested existence of a transcriptional interactome. Here, using a controlled strategy of transgenesis, we analyzed the functional consequences of regulatory sequence interaction within the myelin basic protein (mbp) locus. Interactions were revealed through comparisons of the qualitative and quantitative expression programs conferred by an allelic series of 11 different enhancer/inter-enhancer combinations ligated to a common promoter/reporter gene. In a developmentally contextual manner, the regulatory output of all modules changed markedly in the presence of other sequences. Predicted by transgene expression programs, deletion of one such module from the endogenous locus reduced oligodendrocyte expression levels but unexpectedly, also attenuated expression of the overlapping golli transcriptional unit. These observations support a regulatory architecture that extends beyond a combinatorial model to include frequent interactions capable of significantly modulating the functions conferred through regulatory modules in isolation.

Published
2011
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43. New insights into microtubule elongation mechanisms

Author

Valiron, Odile, INSERM U836, équipe 1, Physiopathologie du cytosquelette, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Andrieux, Annie

Subjects
microtubules, tubulin, tubulin structure, microtubule assembly, macromolecular substances, GTP hydrolysis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mini-Review, nucleotide, General Agricultural and Biological Sciences, microtubule dynamics, [SDV.BC] Life Sciences [q-bio]/Cellular Biology
Abstract

International audience; Microtubules are cytoskeletal structures in the cytoplasm of eukaryotic cells, and their highly dynamic properties are essential to perform a wide variety of vital functions in cells. Microtubule growth proceeds through the endwise addition of nucleotide-bound tubulin molecules. It has largely been assumed that only tubulin dimers can incorporate into microtubules, and that the chemical state of the nucleotide is crucial for the incorporation. Recent observations reveal that both tubulin dimers and oligomers can add to microtubule ends and that the chemical state of the nucleotide is not decisive for tubulin addition. Together with structural studies of tubulin, these results show tubulin assembly polymorphism, which could play a crucial role in microtubule-dependent cellular functions.

Published
2011
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44. Disruption of CK2beta in embryonic neural stem cells compromises proliferation and oligodendrogenesis in the mouse telencephalon

Author

Léa Ziercher, Emmanuelle Huillard, Jean-Christophe Deloulme, Serhiy Souchelnytskyi, Jacques Baudier, Olivier Blond, Claude Cochet, Thierry Buchou, Michael Wong, Department of Pediatrics and Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, Transduction du signal : signalisation calcium, phosphorylation et inflammation, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Karolinska Biomics Center, Karolinska Institutet [Stockholm], Institut National de la Sante et de la Recherche Medicale (INSERM), Commissariat a l'Energie Atomique (CEA), Ligue Nationale Contre le Cancer (Equipe Labelisee 2007), Institut National du Cancer (grant number 57), University of California (UC), and Andrieux, Annie

Subjects
Telencephalon, MESH: Signal Transduction, Cellular differentiation, MESH: Neurons, MESH: Casein Kinase II, MESH: Mice, Knockout, Mice, 0302 clinical medicine, Conditional gene knockout, MESH: Basic Helix-Loop-Helix Transcription Factors, MESH: Gene Expression Regulation, Developmental, Basic Helix-Loop-Helix Transcription Factors, MESH: Animals, MESH: Nerve Tissue Proteins, Casein Kinase II, MESH: Embryonic Stem Cells, Cells, Cultured, Mice, Knockout, Neurons, 0303 health sciences, Gene Expression Regulation, Developmental, Cell Differentiation, MESH: Oligodendroglia, Articles, Neural stem cell, Cell biology, Oligodendroglia, medicine.anatomical_structure, Signal Transduction, MESH: Cells, Cultured, MESH: Cell Differentiation, Nerve Tissue Proteins, Biology, OLIG2, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH: Cell Proliferation, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Progenitor cell, Molecular Biology, Transcription factor, MESH: Mice, Embryonic Stem Cells, Cell Proliferation, 030304 developmental biology, MESH: Biological Markers, MESH: Embryo, Mammalian, Cell Biology, Oligodendrocyte Transcription Factor 2, Embryo, Mammalian, Embryonic stem cell, Molecular biology, Oligodendrocyte, Mice, Inbred C57BL, MESH: Telencephalon, Biomarkers, 030217 neurology & neurosurgery
Abstract

International audience; Genetic programs that govern neural stem/progenitor cell (NSC) proliferation and differentiation are dependent on extracellular cues and a network of transcription factors, which can be regulated posttranslationally by phosphorylation. However, little is known about the kinase-dependent pathways regulating NSC maintenance and oligodendrocyte development. We used a conditional knockout approach to target the murine regulatory subunit (beta) of protein kinase casein kinase 2 (CK2beta) in embryonic neural progenitors. Loss of CK2beta leads to defects in proliferation and differentiation of embryonic NSCs. We establish CK2beta as a key positive regulator for the development of oligodendrocyte precursor cells (OPCs), both in vivo and in vitro. We show that CK2beta directly interacts with the basic helix-loop-helix (bHLH) transcription factor Olig2, a critical modulator of OPC development, and activates the CK2-dependent phosphorylation of its serine-threonine-rich (STR) domain. Finally, we reveal that the CK2-targeted STR domain is required for the oligodendroglial function of Olig2. These findings suggest that CK2 may control oligodendrogenesis, in part, by regulating the activity of the lineage-specific transcription factor Olig2. Thus, CK2beta appears to play an essential and uncompensated role in central nervous system development.

Published
2010
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45. Loss of STOP protein impairs peripheral olfactory neurogenesis

Author

Nelly Boehm, Alice Couegnas, Didier Job, Sebastien Fernandez, Christiane Schaeffer, Annie Schweitzer, Maria-Cristina Antal, Karelle Benardais, Basem Kasem, Annie Andrieux, Astrid Nehlig, Anne Giersch, Brigitte Samama, Andrieux, Annie, Institut d'Histologie, Physiopathologie clinique et expérimentale de la schizophrénie, Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), hôpitaux universitaires de Strasbourg, Hôpitaux Universitaire de Strasbourg, INSERM U836, équipe 1, Physiopathologie du cytosquelette, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Physiopathologie du Cytosquelette (GPC), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Grenoble Institut des Neurosciences (GIN)

Subjects
Male, Olfactory system, Pathology, Vomeronasal organ, lcsh:Medicine, Mice, 0302 clinical medicine, lcsh:Science, Mice, Knockout, Glomerulus (olfaction), Mice, Inbred BALB C, 0303 health sciences, Multidisciplinary, Neurogenesis, Neuroscience/Neurodevelopment, Olfactory Bulb, medicine.anatomical_structure, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Microtubule-Associated Proteins, Research Article, medicine.medical_specialty, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Olfactory Receptor Neurons, 03 medical and health sciences, Olfactory mucosa, Olfactory Mucosa, Cell Biology/Cytoskeleton, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, Mental Health/Schizophrenia and Other Psychoses, Neuroscience/Sensory Systems, lcsh:R, Olfactory bulb, Developmental Biology/Neurodevelopment, Disease Models, Animal, Synapses, Schizophrenia, lcsh:Q, Olfactory ensheathing glia, Olfactory epithelium, Neuroscience, 030217 neurology & neurosurgery
Abstract

BACKGROUND: STOP (Stable Tubulin-Only Polypeptide) null mice show behavioral deficits, impaired synaptic plasticity, decrease in synaptic vesicular pools and disturbances in dopaminergic transmission, and are considered a neurodevelopmental model of schizophrenia. Olfactory neurons highly express STOP protein and are continually generated throughout life. Experimentally-induced loss of olfactory neurons leads to epithelial regeneration within two months, providing a useful model to evaluate the role played by STOP protein in adult olfactory neurogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Immunocytochemistry and electron microscopy were used to study the structure of the glomerulus in the main olfactory bulb and neurogenesis in the neurosensorial epithelia. In STOP null mice, olfactory neurons showed presynaptic swellings with tubulovesicular profiles and autophagic-like structures. In olfactory and vomeronasal epithelia, there was an increase in neurons turnover, as shown by the increase in number of proliferating, apoptotic and immature cells with no changes in the number of mature neurons. Similar alterations in peripheral olfactory neurogenesis have been previously described in schizophrenia patients. In STOP null mice, regeneration of the olfactory epithelium did not modify these anomalies; moreover, regeneration resulted in abnormal organisation of olfactory terminals within the olfactory glomeruli in STOP null mice. CONCLUSIONS/SIGNIFICANCE: In conclusion, STOP protein seems to be involved in the establishment of synapses in the olfactory glomerulus. Our results indicate that the olfactory system of STOP null mice is a well-suited experimental model (1) for the study of the mechanism of action of STOP protein in synaptic function/plasticity and (2) for pathophysiological studies of the mechanisms of altered neuronal connections in schizophrenia.

Published
2010
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46. Role of EG-VEGF in human placentation: Physiological and pathological implications

Author

Jean-Jacques Feige, Jean-Patrick Schaal, Yasmina Saoudi, Mohamed Benharouga, Charles H. Graham, Chafika Mazouni, Nadia Alfaidy, Pascale Hoffmann, Service gynécologie, obstétrique et médecine de reproduction, CHU Grenoble, Angiogenèse hormono-regulée et angiogenèse tumorale (LAPV), Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U836, équipe 1, Physiopathologie du cytosquelette, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Anatomy and Cell Biology, Queen's University, Service de Gynécologie et Obstétrique [Marseille], Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), INSERM U878 CEA Programme National de Recherche en Reproduction et Endocrinologie, Département de Gynécologie, Obstétrique et Médecine de la Reproduction, European Synchrotron Radiation Facility (ESRF)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV) (BIG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Service de Gynécologie Obstétrique, Hôpital Nord [CHU - APHM], Andrieux, Annie, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes (UGA)

Subjects
Adult, medicine.medical_specialty, pre-eclampsia, Placenta, medicine.medical_treatment, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Biology, 03 medical and health sciences, Paracrine signalling, chemistry.chemical_compound, 0302 clinical medicine, MESH: Pregnancy, Pregnancy, trophoblast invasion, Internal medicine, medicine, Humans, EG-VEGF, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, 030304 developmental biology, 0303 health sciences, 030219 obstetrics & reproductive medicine, MESH: Humans, Molecular Target, Growth factor, Decidua, Trophoblast, Placentation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Adult, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Cell Biology, medicine.disease, MESH: Placenta, Vascular endothelial growth factor, prokineticin, medicine.anatomical_structure, Endocrinology, chemistry, MESH: Vascular Endothelial Growth Factor, Endocrine-Gland-Derived, Molecular Medicine, Female, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived, MESH: Female
Abstract

International audience; Pre-eclampsia (PE), the major cause of maternal morbidity and mortality, is thought to be caused by shallow invasion of the maternal decidua by extravillous trophoblasts (EVT). Data suggest that a fine balance between the expressions of pro- and anti-invasive factors might regulate EVT invasiveness. Recently, we showed that the expression of the new growth factor endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is high in early pregnancy but falls after 11 weeks, suggesting an essential role for this factor in early pregnancy. Using human villous explants and HTR-8/SVneo, a first trimester extravillous trophoblast cell line, we showed differential expression of EG-VEGF receptors, PKR1 and PKR2, in the placenta and demonstrated that EG-VEGF inhibits EVT migration, invasion and tube-like organisation. EG-VEGF inhibitory effect on invasion was supported by a decrease in matrix metalloproteinase (MMP)-2 and MMP-9 production. Interference with PKR2 expression, using specific siRNAs, reversed the EG-VEGF-induced inhibitory effects. Furthermore, we determined EG-VEGF circulating levels in normal and PE patients. Our results showed that EG-VEGF levels were highest during the first trimester of pregnancy and decreased thereafter to non-pregnant levels. More important, EG-VEGF levels were significantly elevated in PE patients compared with age-matched controls. These findings identify EG-VEGF as a novel paracrine regulator of trophoblast invasion. We speculate that a failure to correctly down-regulate placental expression of EG-VEGF at the end of the first trimester of pregnancy might lead to PE.

Published
2009
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47. Motor-dependent microtubule disassembly driven by tubulin tyrosination

Author

Laurence Lafanechère, Michael Wagenbach, Didier Job, Annie Andrieux, Linda Wordeman, Jacques Brocard, Ayana T. Moore, Leticia Peris, Frank Kozielski, Groupe Physiopathologie du Cytosquelette (GPC), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Department of Physiology and Biophysics, University of Washington [Seattle], Laboratoire de physiologie cellulaire végétale (LPCV), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Beatson Institute for Cancer Research, Beatson institute for cancer research, La ligue contre le cancer ARC, ANR Blanc Blanc07-2-187328,ANR Blanc Blanc07-2-187328, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), The Beatson Institute for Cancer Research, University of Glasgow, ANR-07-BLAN-0045,Tyr-TIPs,Cell regulations at microtubule +ends: shifting from a Darwinist to a deterministic view of microtubule organization and of cell morphogenesis(2007), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Andrieux, Annie, and Blanc - Cell regulations at microtubule +ends: shifting from a Darwinist to a deterministic view of microtubule organization and of cell morphogenesis - - Tyr-TIPs2007 - ANR-07-BLAN-0045 - BLANC - VALID

Subjects
MESH: Hippocampus, MESH: Molecular Motor Proteins, MESH: Neurons, Kinesins, MESH: Tubulin, Hippocampus, Microtubules, MESH: Mice, Knockout, Mitotic Spindle Apparatus, MESH: Tyrosine, Mice, chemistry.chemical_compound, 0302 clinical medicine, Tubulin, MESH: Animals, Cytoskeleton, Cells, Cultured, Research Articles, Mice, Knockout, Neurons, 0303 health sciences, Cultured, biology, MESH: Microtubules, Molecular Motor Proteins, Nocodazole, Kinesin, Tubulin Modulators, Cell biology, MESH: Cells, Cultured, Knockout, Recombinant Fusion Proteins, Cells, Spindle Apparatus, macromolecular substances, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Nocodazole, 03 medical and health sciences, Microtubule, Report, Detyrosination, MESH: Tubulin Modulators, MESH: Recombinant Fusion Proteins, Animals, MESH: Cell Shape, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cell Shape, MESH: Mice, 030304 developmental biology, MESH: Mitotic Spindle Apparatus, Microtubule Depolymerization Process, Cell Biology, Fibroblasts, chemistry, MESH: Fibroblasts, biology.protein, Tyrosine, MESH: Kinesin, 030217 neurology & neurosurgery
Abstract

International audience; In cells, stable microtubules (MTs) are covalently modified by a carboxypeptidase, which removes the C-terminal Tyr residue of alpha-tubulin. The significance of this selective detyrosination of MTs is not understood. In this study, we report that tubulin detyrosination in fibroblasts inhibits MT disassembly. This inhibition is relieved by overexpression of the depolymerizing motor mitotic centromere-associated kinesin (MCAK). Conversely, suppression of MCAK expression prevents disassembly of normal tyrosinated MTs in fibroblasts. Detyrosination of MTs suppresses the activity of MCAK in vitro, apparently as the result of a decreased affinity of the adenosine diphosphate (ADP)-inorganic phosphate- and ADP-bound forms of MCAK for the MT lattice. Detyrosination also impairs MT disassembly in neurons and inhibits the activity of the neuronal depolymerizing motor KIF2A in vitro. These results indicate that MT depolymerizing motors are directly inhibited by the detyrosination of tubulin, resulting in the stabilization of cellular MTs. Detyrosination of transiently stabilized MTs may give rise to persistent subpopulations of disassembly-resistant polymers to sustain subcellular cytoskeletal differentiation.

Published
2009
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48. STOP proteins contribute to the maturation of the olfactory system

Author

Annie Schweitzer, Marion Richard, François Jourdan, Véronique Pellier-Monnin, Joëlle Sacquet, Annie Andrieux, Marion Jany, Neurosciences Sensorielles Comportement Cognition, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), IFR des neurosciences de Lyon (IFNL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Centre Hospitalier le Vinatier [Bron]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Andrieux, Annie

Subjects
Olfactory system, MESH: Protein Isoforms, Microtubules, MESH: Mice, Knockout, MESH: Vomeronasal Organ, Tissue Culture Techniques, Mice, 0302 clinical medicine, Olfactory bulb, MESH: Pregnancy, Olfactory nerve, Pregnancy, Protein Isoforms, MESH: Animals, MESH: Nerve Tissue Proteins, Cytoskeleton, Mice, Knockout, Mice, Inbred BALB C, 0303 health sciences, Olfactory Pathways, Cell biology, medicine.anatomical_structure, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Vomeronasal Organ, Microtubule-Associated Proteins, MESH: Rats, MESH: Mice, Inbred BALB C, Nerve Tissue Proteins, Sensory system, Biology, Olfactory Receptor Neurons, 03 medical and health sciences, Cellular and Molecular Neuroscience, Microtubule, Neuropil, medicine, Animals, Axon outgrowth, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Tissue Culture Techniques, Rats, Wistar, Molecular Biology, MESH: Mice, 030304 developmental biology, Cell Biology, MESH: Rats, Wistar, MESH: Olfactory Receptor Neurons, Rats, MESH: Microtubule-Associated Proteins, nervous system, Olfactory ensheathing glia, Neuroscience, MESH: Female, 030217 neurology & neurosurgery, MESH: Olfactory Pathways
Abstract

International audience; Regulation of microtubule dynamics is crucial for axon growth and guidance as well as for the establishment of synaptic connections. STOPs (Stable Tubule Only Polypeptides) are microtubule-associated proteins that regulate microtubule stabilization but are also able to interact with actin or Golgi membranes. Here, we have investigated the involvement of STOPs during the development of the olfactory system. We first describe the spatio-temporal expression patterns of N- and E-STOP, the two neuronal-specific isoforms of STOP. E- and N-STOP are expressed in the axonal compartment of olfactory sensory neurons, but are differentially regulated during development. Interestingly, each neuronal isoform displays a specific gradient distribution within the olfactory nerve layer. Then, we have examined the development of the olfactory system in the absence of STOPs. Olfactory axons display a normal outgrowth and targeting in STOP-null mice, but maturation of the synapses in the glomerular neuropil is altered.

Published
2009
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49. Tubulin tyrosination is required for the proper organization and pathfinding of the growth cone

Author

Julie L. M. Moreau, Stéphanie Backer, Didier Job, Annie Andrieux, Séverine Marcos, Evelyne Bloch-Gallego, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Collaboration, Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF) - CHU Grenoble - Institut National de la Santé et de la Recherche Médicale (INSERM), and Andrieux, Annie

Subjects
MESH : Tyrosine, rac1 GTP-Binding Protein, MESH : Actins, lcsh:Medicine, MESH: Tubulin, GTP Phosphohydrolases, MESH: Tyrosine, MESH : Cytoskeleton, Mice, 0302 clinical medicine, Tubulin, Myosin, MESH: Animals, Cytoskeleton, lcsh:Science, MESH: Nonmuscle Myosin Type IIB, 0303 health sciences, Multidisciplinary, Nonmuscle Myosin Type IIB, biology, MESH : Tubulin, Neuroscience/Neurodevelopment, Cell biology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Collapsin response mediator protein family, Filopodia, Research Article, MESH: Axons, MESH: GTP Phosphohydrolases, Neurite, Cell Biology/Neuronal Signaling Mechanisms, Growth Cones, Cell Biology/Developmental Molecular Mechanisms, MESH : Axons, macromolecular substances, MESH : Growth Cones, MESH: Actins, 03 medical and health sciences, MESH : rac1 GTP-Binding Protein, Microtubule, Cell Biology/Cytoskeleton, MESH : Mice, Neuroscience/Neuronal Signaling Mechanisms, MESH: Cytoskeleton, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Growth cone, MESH: Mice, 030304 developmental biology, MESH : Protein Processing, Post-Translational, MESH : Nonmuscle Myosin Type IIB, MESH: rac1 GTP-Binding Protein, lcsh:R, MESH: Growth Cones, Actins, Axons, Developmental Biology/Neurodevelopment, MESH: Protein Processing, Post-Translational, biology.protein, Developmental Biology/Cell Differentiation, Tyrosine, lcsh:Q, MESH : Animals, MESH : GTP Phosphohydrolases, Protein Processing, Post-Translational, 030217 neurology & neurosurgery
Abstract

International audience; BACKGROUND: During development, neuronal growth cones integrate diffusible and contact guidance cues that are conveyed to both actin and microtubule (MT) cytoskeletons and ensure axon outgrowth and pathfinding. Although several post-translational modifications of tubulin have been identified and despite their strong conservation among species, their physiological roles during development, especially in the nervous sytem, are still poorly understood. METHODOLOGY/FINDINGS: Here, we have dissected the role of a post-translational modification of the last amino acid of the alpha-tubulin on axonal growth by analyzing the phenotype of precerebellar neurons in Tubulin tyrosin ligase knock-out mice (TTL(-/-)) through in vivo, ex vivo and in vitro analyses. TTL(-/-) neurons are devoid of tyrosinated tubulin. Their pathway shows defects in vivo, ex vivo, in hindbrains open-book preparations or in vitro, in a collagen matrix. Their axons still orient toward tropic cues, but they emit supernumerary branches and their growth cones are enlarged and exhibit an emission of mis-oriented filopodia. Further analysis of the TTL(-/-) growth cone intracellular organization also reveals that the respective localization of actin and MT filaments is disturbed, with a decrease in the distal accumulation of Myosin IIB, as well as a concomitant Rac1 over-activation in the hindbrain. Pharmacological inhibition of Rac1 over-activation in TTL(-/-) neurons can rescue Myosin IIB localization. CONCLUSIONS/SIGNIFICANCE: In the growth cone, we propose that tubulin tyrosination takes part in the relative arrangement of actin and MT cytoskeletons, in the regulation of small GTPases activity, and consequently, in the proper morphogenesis, organization and pathfinding of the growth cone during development.

Published
2009
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50. Dual role of CD38 in microglial activation and activation-induced cell death

Author

Gideon Rechavi, Jasmine Jacob-Hirsch, Marie-Jo Moutin, Lior Mayo, Frances E. Lund, Reuven Stein, Ninette Amariglio, Department of Neurobiology, Tel Aviv University [Tel Aviv], Department of Pediatric Hematology-Oncology, Tel Aviv University [Tel Aviv]-Sheba Medical Center-Safra Children's Hospital-Tel Hashomer and Sackler Faculty of Medicine, ANTE-INSERM U836, équipe 1, Physiopathologie du cytosquelette, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Trudeau Institute, Collaboration, Tel Aviv University (TAU), Tel Aviv University (TAU)-Sheba Medical Center-Safra Children's Hospital-Tel Hashomer and Sackler Faculty of Medicine, and Andrieux, Annie

Subjects
Lipopolysaccharides, MESH: Cell Death, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, CD38, MESH: Mice, Knockout, Calcium in biology, Mice, 0302 clinical medicine, Immunology and Allergy, MESH: Animals, Caspase, Cells, Cultured, Oligonucleotide Array Sequence Analysis, Mice, Knockout, 0303 health sciences, Mice, Inbred BALB C, biology, Microglia, Cell Death, MESH: Gene Expression Regulation, Caspases, Initiator, 3. Good health, Cell biology, MESH: Microglia, medicine.anatomical_structure, Caspases, MESH: Cells, Cultured, Programmed cell death, MESH: Interferon-gamma, Immunology, MESH: Mice, Inbred BALB C, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Nitric Oxide, Article, 03 medical and health sciences, Interferon-gamma, Immune system, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Secretion, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, 030304 developmental biology, MESH: Caspases, MESH: Antigens, CD38, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, ADP-ribosyl Cyclase 1, Gene Expression Regulation, Apoptosis, MESH: Nitric Oxide, MESH: Oligonucleotide Array Sequence Analysis, biology.protein, MESH: Lipopolysaccharides, 030217 neurology & neurosurgery
Abstract

Microglia, the resident immune cells of the CNS, are normally quiescent but become activated after infection or injury. Their properties then change, and they promote both repair and damage processes. The extent of microglial activation is regulated, in part, by activation-induced cell death (AICD). Although many apoptotic aspects of the microglial AICD mechanism have been elucidated, little is known about the connection between the activation step and the death process. Using mouse primary microglial cultures, we show that the ectoenzyme CD38, via its calcium-mobilizing metabolite cyclic-ADP-ribose (cADPR), helps promote microglial activation and AICD induced by LPS plus IFN-γ (LPS/IFN-γ), suggesting that CD38 links the two processes. Accordingly, CD38 expression and activity, as well as the intracellular calcium concentration ([Ca2+]i) in the primary microglia were increased by LPS/IFN-γ treatment. Moreover, CD38 deficiency or treatment with cADPR antagonists conferred partial resistance to LPS/IFN-γ-induced AICD and also reduced [Ca2+]i. Microglial activation, indicated by induced expression of NO synthase-2 mRNA and production of NO, secretion and mRNA expression of TNF-α and IL-12 p40, and expression of IL-6 mRNA, was attenuated by CD38 deficiency or cADPR-antagonist treatment. The observed effects of CD38 on microglial activation are probably mediated via a cADPR-dependent increase in [Ca2+]i and the effect on AICD by regulation of NO production. Our results thus suggest that CD38 significantly affects regulation of the amount and function of activated microglia, with important consequences for injury and repair processes in the brain.

Published
2008

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