title: miR-124 Contributes to the functional maturity of microglia.
abstract: During early development of the central nervous system (CNS), a subset of yolk-sac derived myeloid cells populate the brain and provide the seed for the microglial cell population, which will self-renew throughout life. As development progresses, individual microglial cells transition from a phagocytic amoeboid state through a transitional morphing phase into the sessile, ramified, and normally nonphagocytic microglia observed in the adult CNS under healthy conditions. The molecular drivers of this tissue-specific maturation profile are not known. However, a survey of tissue resident macrophages identified miR-124 to be expressed in microglia. In this study, we used transgenic zebrafish to overexpress miR-124 in the mpeg1 expressing yolk-sac-derived myeloid cells that seed the microglia. In addition, a systemic sponge designed to neutralize the effects of miR-124 was used to assess microglial development in a miR-124 loss-of-function environment. Following the induction of miR-124 overexpression, microglial motility and phagocytosis of apoptotic cells were significantly reduced. miR-124 overexpression in microglia resulted in the accumulation of residual apoptotic cell bodies in the optic tectum, which could not be achieved by miR-124 overexpression in differentiated neurons. Conversely, expression of the miR-124 sponge caused an increase in the motility of microglia and transiently rescued motility and phagocytosis functions when activated simultaneously with miR-124 overexpression. This study provides in vivo evidence that miR-124 activity has a key role in the development of functionally mature microglia.
authors.affiliation: Brain and Mind Research Institute, Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Svahn
authors.affiliation: Brain and Mind Research Institute, Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Jean
authors.initials: J
authors.lastname: Giacomotto
authors.affiliation: Brain and Mind Research Institute, Sydney Medical School, University of Sydney, Sydney, Australia.|Faculty of Health Sciences, University of Sydney, Sydney, Australia.
authors.forename: Manuel B
authors.initials: MB
authors.lastname: Graeber
authors.affiliation: Brain and Mind Research Institute, Sydney Medical School, University of Sydney, Sydney, Australia.|Department of Physiology and School of Medicine, University of Sydney, Sydney, Australia.
authors.forename: Silke
authors.initials: S
authors.lastname: Rinkwitz
authors.affiliation: Brain and Mind Research Institute, Sydney Medical School, University of Sydney, Sydney, Australia.|Department of Physiology and School of Medicine, University of Sydney, Sydney, Australia.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Becker
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D055785:Gene Knockdown Techniques; D008264:Macrophages / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010587:Phagocytosis / Q000502:physiology; D017385:Sequence Homology; D013477:Superior Colliculi / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D035683:MicroRNAs; D029961:Zebrafish Proteins; C000613215:miR-124, zebrafish; C000603636:mpeg1.1 protein, zebrafish
keywords: chemotaxis; development; miRNA; microglia; phagocytosis