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      Translation in astrocyte distal processes sets molecular heterogeneity at the gliovascular interface

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          Abstract

          Astrocytes send out long processes that are terminated by endfeet at the vascular surface and regulate vascular functions as well as homeostasis at the vascular interface. To date, the astroglial mechanisms underlying these functions have been poorly addressed. Here we demonstrate that a subset of messenger RNAs is distributed in astrocyte endfeet. We identified, among this transcriptome, a pool of messenger RNAs bound to ribosomes, the endfeetome, that primarily encodes for secreted and membrane proteins. We detected nascent protein synthesis in astrocyte endfeet. Finally, we determined the presence of smooth and rough endoplasmic reticulum and the Golgi apparatus in astrocyte perivascular processes and endfeet, suggesting for local maturation of membrane and secreted proteins. These results demonstrate for the first time that protein synthesis occurs in astrocyte perivascular distal processes that may sustain their structural and functional polarization at the vascular interface.

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          Most cited references42

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          A translational profiling approach for the molecular characterization of CNS cell types.

          The cellular heterogeneity of the brain confounds efforts to elucidate the biological properties of distinct neuronal populations. Using bacterial artificial chromosome (BAC) transgenic mice that express EGFP-tagged ribosomal protein L10a in defined cell populations, we have developed a methodology for affinity purification of polysomal mRNAs from genetically defined cell populations in the brain. The utility of this approach is illustrated by the comparative analysis of four types of neurons, revealing hundreds of genes that distinguish these four cell populations. We find that even two morphologically indistinguishable, intermixed subclasses of medium spiny neurons display vastly different translational profiles and present examples of the physiological significance of such differences. This genetically targeted translating ribosome affinity purification (TRAP) methodology is a generalizable method useful for the identification of molecular changes in any genetically defined cell type in response to genetic alterations, disease, or pharmacological perturbations.
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            Application of a translational profiling approach for the comparative analysis of CNS cell types.

            Comparative analysis can provide important insights into complex biological systems. As demonstrated in the accompanying paper, translating ribosome affinity purification (TRAP) permits comprehensive studies of translated mRNAs in genetically defined cell populations after physiological perturbations. To establish the generality of this approach, we present translational profiles for 24 CNS cell populations and identify known cell-specific and enriched transcripts for each population. We report thousands of cell-specific mRNAs that were not detected in whole-tissue microarray studies and provide examples that demonstrate the benefits deriving from comparative analysis. To provide a foundation for further biological and in silico studies, we provide a resource of 16 transgenic mouse lines, their corresponding anatomic characterization, and translational profiles for cell types from a variety of central nervous system structures. This resource will enable a wide spectrum of molecular and mechanistic studies of both well-known and previously uncharacterized neural cell populations.
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              Emerging roles of astrocytes in neural circuit development.

              Astrocytes are now emerging as key participants in many aspects of brain development, function and disease. In particular, new evidence shows that astrocytes powerfully control the formation, maturation, function and elimination of synapses through various secreted and contact-mediated signals. Astrocytes are also increasingly being implicated in the pathophysiology of many psychiatric and neurological disorders that result from synaptic defects. A better understanding of how astrocytes regulate neural circuit development and function in the healthy and diseased brain might lead to the development of therapeutic agents to treat these diseases.
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                Author and article information

                Journal
                Cell Discov
                Cell Discov
                Cell Discovery
                Nature Publishing Group
                2056-5968
                28 March 2017
                2017
                : 3
                : 17005
                Affiliations
                [1 ]Neuroglial Interactions in Cerebral Physiopathology/Collège de France, Center for Interdisciplinary Research in Biology (CIRB)/Centre National de la Recherche Scientifique CNRS, UMR 7241/Institut National de la Santé et de la Recherche Médicale INSERM, U1050/University Pierre et Marie Curie UPMC, ED, No. 158/MEMOLIFE Laboratory of Excellence and PSL Research University , Paris, France
                [2 ]Variabilité des réponses aux psychotropes, INSERM U1144/Faculté de Pharmacie de Paris/Université Paris Descartes/Université Paris Diderot/Université Sorbonne Paris Cité , Paris, France
                [3 ]Cellular and Molecular Imaging Facility, INSERM US25/CNRS UMS 3612/Faculté de Pharmacie de Paris/Université Paris Descartes/Université Sorbonne Paris Cité , Paris, France
                [4 ]Institut Pasteur, Human Histopathology and Animal Models , Paris, France
                [5 ]Université Paris Descartes–Sorbonne Paris Cité , Paris, France
                [6 ]Service de Neuropathologie, Centre Hospitalier Sainte-Anne , Paris, France
                [7 ]Plateforme Bioinformatique, Ecole Normale Supérieure/Institut de Biologie de l’ENS (IBENS) /INSERM, U1024/CNRS, UMR 8197 , Paris, France
                [8 ]Plateforme Génomique, Ecole Normale Supérieure/PSL Research University/IBENS/INSERM/CNRS , Paris, France
                [9 ]Plateforme de qPCR à Haut Débit, Ecole Normale Supérieure/IBENS , Paris, France
                [10 ]Laboratoire de Physique Statistique, ENS/CNRS UMR 8550/PSL Research University/Université Paris Diderot Sorbonne Paris-Cité/Sorbonne Universités UPMC , Paris, France
                [11 ]Evolution Paris Seine, Institut de Biologie Paris-Seine (IBPS)/Sorbonne Universités, UPMC/CNRS UMR 7138 , Paris, France
                Author notes
                [* ] Tel: +33 144 271 242; Fax: +33 (0) 44 27 12 68 E-mail: martine.cohen-salmon@ 123456college-de-france.fr

                A-CB, BS and MC-S designed research; A-CB, BS, NA, SC, CB, NM, AG, JP and MC-S performed research; A-CB, BS, NA, MB, LB, SP and MC-S analyzed data; FC, J-LL, XD and MC-S provided resources; AG, SLC, BD and MC-S. supervised the study; MC-S wrote the paper.

                Author information
                http://orcid.org/0000-0002-5312-8476
                Article
                celldisc20175
                10.1038/celldisc.2017.5
                5368712
                28377822
                a0d3db9a-e28c-4134-a7d9-280576e52854
                Copyright © 2017 The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 28 October 2016
                : 10 January 2017
                Categories
                Article

                astrocyte,gliovascular unit,endfeet,translating ribosome immunoprecipitation,local translation,mrnas localization

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