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      Coupled Proliferation and Apoptosis Maintain the Rapid Turnover of Microglia in the Adult Brain

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          Summary

          Microglia play key roles in brain development, homeostasis, and function, and it is widely assumed that the adult population is long lived and maintained by self-renewal. However, the precise temporal and spatial dynamics of the microglial population are unknown. We show in mice and humans that the turnover of microglia is remarkably fast, allowing the whole population to be renewed several times during a lifetime. The number of microglial cells remains steady from late postnatal stages until aging and is maintained by the spatial and temporal coupling of proliferation and apoptosis, as shown by pulse-chase studies, chronic in vivo imaging of microglia, and the use of mouse models of dysregulated apoptosis. Our results reveal that the microglial population is constantly and rapidly remodeled, expanding our understanding of its role in the maintenance of brain homeostasis.

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          Highlights

          • The microglial population is formed without the perinatal infiltration of monocytes

          • The microglial density remains remarkably stable over a mouse or human lifetime

          • In the mouse and human brain, microglia turn over several times during a lifetime

          • Microglia self-renewal is maintained by coupled proliferation and apoptosis

          Abstract

          The mechanism or mechanisms underlying microglial homeostasis are unknown. Askew et al. show that microglia self-renewal is maintained by coupled proliferation and apoptosis, resulting in a stable microglia number over a mouse or human lifetime.

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          Most cited references 17

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          Microglia regulate the number of neural precursor cells in the developing cerebral cortex.

          Neurogenesis must be properly regulated to ensure that cell production does not exceed the requirements of the growing cerebral cortex, yet our understanding of mechanisms that restrain neuron production remains incomplete. We investigated the function of microglial cells in the developing cerebral cortex of prenatal and postnatal macaques and rats and show that microglia limit the production of cortical neurons by phagocytosing neural precursor cells. We show that microglia selectively colonize the cortical proliferative zones and phagocytose neural precursor cells as neurogenesis nears completion. We found that deactivating microglia in utero with tetracyclines or eliminating microglia from the fetal cerebral cortex with liposomal clodronate significantly increased the number of neural precursor cells, while activating microglia in utero through maternal immune activation significantly decreased the number of neural precursor cells. These data demonstrate that microglia play a fundamental role in regulating the size of the precursor cell pool in the developing cerebral cortex, expanding our understanding of the mechanisms that regulate cortical development. Furthermore, our data suggest that any factor that alters the number or activation state of microglia in utero can profoundly affect neural development and affect behavioral outcomes.
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            Recruitment of beneficial M2 macrophages to injured spinal cord is orchestrated by remote brain choroid plexus.

            Monocyte-derived macrophages are essential for recovery after spinal cord injury, but their homing mechanism is poorly understood. Here, we show that although of common origin, the homing of proinflammatory (M1) and the "alternatively activated" anti-inflammatory (M2) macrophages to traumatized spinal cord (SC) was distinctly regulated, neither being through breached blood-brain barrier. The M1 macrophages (Ly6c(hi)CX3CR1(lo)) derived from monocytes homed in a CCL2 chemokine-dependent manner through the adjacent SC leptomeninges. The resolving M2 macrophages (Ly6c(lo)CX3CR1(hi)) derived from monocytes trafficked through a remote blood-cerebrospinal-fluid (CSF) barrier, the brain-ventricular choroid plexus (CP), via VCAM-1-VLA-4 adhesion molecules and epithelial CD73 enzyme for extravasation and epithelial transmigration. Blockage of these determinants, or mechanical CSF flow obstruction, inhibited M2 macrophage recruitment and impaired motor-function recovery. The CP, along with the CSF and the central canal, provided an anti-inflammatory supporting milieu, potentially priming the trafficking monocytes. Overall, our finding demonstrates that the route of monocyte entry to central nervous system provides an instructional environment to shape their function. Copyright © 2013 Elsevier Inc. All rights reserved.
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              The utility of Ki-67 and BrdU as proliferative markers of adult neurogenesis.

              Adult animals continue to produce new neurons in the dentate gyrus of hippocampus. Until now, the principal method of studying neurogenesis has been to inject either tritiated thymidine or 5'-Bromo-2-deoxyuridine (BrdU) intraperitoneally followed by autoradiographic or immunohistochemical detection methods respectively. However, such exogenous markers may produce toxic effects. Our objective was to determine whether Ki-67, a nuclear protein expressed in all phases of the cell cycle except the resting phase, can be used as an alternative, endogenous marker. Using immunohistochemistry, we examined Ki-67 and BrdU expression pattern in rats. Ki-67 was expressed within the proliferative zone of the dentate gyrus and its expression pattern mimicked that of BrdU when examined soon after exogenous BrdU administration. Quantitative comparison of BrdU and Ki-67-positive cells showed 50% higher numbers of the latter when examined 24 h after the BrdU injection. This was expected, since BrdU can be incorporated into DNA only during the S-phase of the mitotic process, whereas Ki-67 is expressed for its whole duration. Experimental increases (by ischemia) or reductions (by radiation) in the number of mitotic cells produced parallel changes in BrdU and Ki-67 signals. Thus, Ki-67 is an effective mitotic marker and has most of the benefits of BrdU and none of the costs. This study provides evidence for Ki-67 to be used as a marker of proliferation in the initial phase of adult neurogenesis.
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                Author and article information

                Contributors
                Journal
                Cell Rep
                Cell Rep
                Cell Reports
                Cell Press
                2211-1247
                10 January 2017
                10 January 2017
                10 January 2017
                : 18
                : 2
                : 391-405
                Affiliations
                [1 ]Biological Sciences, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK
                [2 ]Institute of Physiology II, University of Tübingen, 72074 Tübingen, Germany
                [3 ]Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PA, UK
                [4 ]Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton, Southampton SO16 6YD, UK
                [5 ]Research Department Cell and Gene Therapy, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
                [6 ]Achucarro Basque Center for Neuroscience, Ikerbasque Foundation, University of the Basque Country (UPV/EHU), 48940 Leioa, Bizkaia, Spain
                Author notes
                []Corresponding author d.gomez-nicola@ 123456soton.ac.uk
                [7]

                Lead Contact

                Article
                S2211-1247(16)31746-6
                10.1016/j.celrep.2016.12.041
                5263237
                28076784
                © 2017 The Author(s)

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                Categories
                Article

                Cell biology

                self-renewal, brdu, csf1r, cx3cr1, macgreen, vav-bcl2, rna-seq

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