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      Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice : Role of miR-155 in ALS

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          Abstract

          To investigate miR-155 in the SOD1 mouse model and human sporadic and familial amyotrophic lateral sclerosis (ALS).

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          Most cited references61

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          Fate mapping analysis reveals that adult microglia derive from primitive macrophages.

          Microglia are the resident macrophages of the central nervous system and are associated with the pathogenesis of many neurodegenerative and brain inflammatory diseases; however, the origin of adult microglia remains controversial. We show that postnatal hematopoietic progenitors do not significantly contribute to microglia homeostasis in the adult brain. In contrast to many macrophage populations, we show that microglia develop in mice that lack colony stimulating factor-1 (CSF-1) but are absent in CSF-1 receptor-deficient mice. In vivo lineage tracing studies established that adult microglia derive from primitive myeloid progenitors that arise before embryonic day 8. These results identify microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders.
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            Identification of a Unique TGF-β Dependent Molecular and Functional Signature in Microglia

            Microglia are myeloid cells of the central nervous system (CNS) that participate both in normal CNS function and disease. We investigated the molecular signature of microglia and identified 239 genes and 8 microRNAs that were uniquely or highly expressed in microglia vs. myeloid and other immune cells. Out of 239 genes, 106 were enriched in microglia as compared to astrocytes, oligodendrocytes and neurons. This microglia signature was not observed in microglial lines or in monocytes recruited to the CNS and was also observed in human microglia. Based on this signature, we found a crucial role for TGF-β in microglial biology that included: 1) the requirement of TGF-β for the in vitro development of microglia that express the microglial molecular signature characteristic of adult microglia; and 2) the absence of microglia in CNS TGF-β1 deficient mice. Our results identify a unique microglial signature that is dependent on TGF-β signaling which provides insights into microglial biology and the possibility of targeting microglia for the treatment of CNS disease.
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              The P2Y12 receptor regulates microglial activation by extracellular nucleotides.

              Microglia are primary immune sentinels of the CNS. Following injury, these cells migrate or extend processes toward sites of tissue damage. CNS injury is accompanied by release of nucleotides, serving as signals for microglial activation or chemotaxis. Microglia express several purinoceptors, including a G(i)-coupled subtype that has been implicated in ATP- and ADP-mediated migration in vitro. Here we show that microglia from mice lacking G(i)-coupled P2Y(12) receptors exhibit normal baseline motility but are unable to polarize, migrate or extend processes toward nucleotides in vitro or in vivo. Microglia in P2ry(12)(-/-) mice show significantly diminished directional branch extension toward sites of cortical damage in the living mouse. Moreover, P2Y(12) expression is robust in the 'resting' state, but dramatically reduced after microglial activation. These results imply that P2Y(12) is a primary site at which nucleotides act to induce microglial chemotaxis at early stages of the response to local CNS injury.
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                Author and article information

                Journal
                Annals of Neurology
                Ann Neurol.
                Wiley
                03645134
                January 2015
                January 2015
                November 27 2014
                : 77
                : 1
                : 75-99
                Affiliations
                [1 ]Ann Romney Center for Neurologic Diseases; Department of Neurology, Brigham and Women's Hospital, Harvard Medical School; Boston MA
                [2 ]Evergrande Center for Immunologic Diseases; Brigham and Women's Hospital, Harvard Medical School; Boston MA 02112
                [3 ]Department of Cell Biology; Harvard Medical School; Boston MA
                [4 ]Institute of Neuropathology, University Medical Center Hamburg-Eppendorf; Hamburg Germany
                [5 ]Department of Neurology; Massachusetts General Hospital; Neurological Clinical Research Institute, Harvard Medical School; Boston MA
                [6 ]Massachusetts General Hospital Alzheimer's Disease Research Center, Harvard University; Boston MA
                [7 ]Program in Translational NeuroPsychiatric Genomics; Brigham and Women's Hospital, Harvard Medical School, Broad Institute of Massachusetts Institute of Technology and Harvard; Cambridge MA
                [8 ]Center for Brain Research, Medical University of Vienna; Vienna Austria
                Article
                10.1002/ana.24304
                25381879
                f2b1f372-c615-46b9-85e8-251851ef565a
                © 2014

                http://doi.wiley.com/10.1002/tdm_license_1.1

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