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Regulation of postnatal forebrain amoeboid microglial cell proliferation and development by the transcription factor Runx1.

Abstract

Microglia are the immune cells of the nervous system, where they act as resident macrophages during inflammatory events underlying many neuropathological conditions. Microglia derive from primitive myeloid precursors that colonize the nervous system during embryonic development. In the postnatal brain, microglia are initially mitotic, rounded in shape (amoeboid), and phagocytically active. As brain development proceeds, they gradually undergo a transition to a surveillant nonphagocytic state characterized by a highly branched (ramified) morphology. This ramification process is almost recapitulated in reverse during the process of microglia activation in the adult brain, when surveillant microglia undergo a ramified-to-amoeboid morphological transformation and become phagocytic in response to injury or disease. Little is known about the mechanisms controlling amoeboid microglial cell proliferation, activation, and ramification during brain development, despite the critical role of these processes in the establishment of the adult microglia pool and their relevance to microglia activation in the adult brain. Here we show that the mouse transcription factor Runx1, a key regulator of myeloid cell proliferation and differentiation, is expressed in forebrain amoeboid microglia during the first two postnatal weeks. Runx1 expression is then downregulated in ramified microglia. Runx1 inhibits mouse amoeboid microglia proliferation and promotes progression to the ramified state. We show further that Runx1 expression is upregulated in microglia following nerve injury in the adult mouse nervous system. These findings provide insight into the regulation of postnatal microglia activation and maturation to the ramified state and have implications for microglia biology in the developing and injured brain.

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    MeSH

    Animals
    Animals, Newborn
    Antigens, CD11b
    Antigens, Differentiation
    Bromodeoxyuridine
    Calcium-Binding Proteins
    Cell Line, Transformed
    Cell Proliferation
    Cells, Cultured
    Chromatin Immunoprecipitation
    Core Binding Factor Alpha 2 Subunit
    Cyclin-Dependent Kinase Inhibitor p21
    Embryo, Mammalian
    Female
    Gene Expression Regulation, Developmental
    Green Fluorescent Proteins
    Humans
    Intermediate Filament Proteins
    Ki-67 Antigen
    Male
    Mice
    Mice, Inbred C57BL
    Mice, Knockout
    Microfilament Proteins
    Microglia
    Nerve Tissue Proteins
    Nestin
    Nitric Oxide Synthase Type II
    Phosphatidylethanolamines
    Prosencephalon
    Sciatic Neuropathy
    Spinal Cord

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22895712