title: Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain.
abstract: The colony-stimulating factor 1 receptor (CSF1R) is a key regulator of myeloid lineage cells. Genetic loss of the CSF1R blocks the normal population of resident microglia in the brain that originates from the yolk sac during early development. However, the role of CSF1R signaling in microglial homeostasis in the adult brain is largely unknown. To this end, we tested the effects of selective CSF1R inhibitors on microglia in adult mice. Surprisingly, extensive treatment results in elimination of ∼99% of all microglia brain-wide, showing that microglia in the adult brain are physiologically dependent upon CSF1R signaling. Mice depleted of microglia show no behavioral or cognitive abnormalities, revealing that microglia are not necessary for these tasks. Finally, we discovered that the microglia-depleted brain completely repopulates with new microglia within 1 week of inhibitor cessation. Microglial repopulation throughout the CNS occurs through proliferation of nestin-positive cells that then differentiate into microglia.
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697-4545, USA.
authors.forename: Monica R P
authors.initials: MR
authors.lastname: Elmore
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697-4545, USA.
authors.forename: Allison R
authors.initials: AR
authors.lastname: Najafi
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697-4545, USA.
authors.forename: Maya A
authors.initials: MA
authors.lastname: Koike
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697-4545, USA.
authors.forename: Nabil N
authors.initials: NN
authors.lastname: Dagher
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697-4545, USA.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Spangenberg
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697-4545, USA.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Rice
authors.affiliation: Department of Molecular and Cell Biology, University of California, Merced, Merced, CA 95343, USA.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kitazawa
authors.affiliation: Plexxikon Inc., Berkeley, CA 94710, USA.
authors.forename: Bernice
authors.initials: B
authors.lastname: Matusow
authors.affiliation: Plexxikon Inc., Berkeley, CA 94710, USA.
authors.forename: Hoa
authors.initials: H
authors.lastname: Nguyen
authors.affiliation: Plexxikon Inc., Berkeley, CA 94710, USA.
authors.forename: Brian L
authors.initials: BL
authors.lastname: West
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697-4545, USA. Electronic address: kngreen@uci.edu.
authors.forename: Kim N
authors.initials: KN
authors.lastname: Green
mesh_terms: D053687:Adult Stem Cells / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor
references.citation: Blood. 2012 Oct 11;120(15):3126-35
references.pmid: 22923495
references.citation: PLoS One. 2011;6(10):e26317
references.pmid: 22046273
references.citation: Exp Mol Pathol. 2000 Dec;69(3):192-201
references.pmid: 11115360
references.citation: Glia. 2004 Jan 1;45(1):96-104
references.pmid: 14648550
references.citation: PLoS One. 2010 Oct 27;5(10):e13693
references.pmid: 21060874
references.citation: Nat Protoc. 2010 Sep;5(9):1481-94
references.pmid: 20725065
references.citation: Acta Neuropathol. 2013 Jan;125(1):159-68
references.pmid: 23099891
references.citation: Dev Biol. 2012 Jul 15;367(2):100-13
references.pmid: 22542597
references.citation: Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5689-94
references.pmid: 23493555
references.citation: Science. 2008 May 9;320(5877):807-11
references.pmid: 18467591
references.citation: Immunity. 2013 Apr 18;38(4):792-804
references.pmid: 23601688
references.citation: J Bone Miner Res. 2014 Feb;29(2):304-15
references.pmid: 23857747
references.citation: J Neurosci. 2011 Nov 9;31(45):16241-50
references.pmid: 22072675
references.citation: Nat Neurosci. 2007 Dec;10(12):1544-53
references.pmid: 18026096
references.citation: Curr Top Med Chem. 2009;9(7):599-610
references.pmid: 19689368
references.citation: Mol Med. 2012 May 09;18:519-27
references.pmid: 22294205
references.citation: Cell. 2013 Dec 19;155(7):1596-609
references.pmid: 24360280
references.citation: Science. 2013 Nov 22;342(6161):1242974
references.pmid: 24264994
references.citation: Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16078-83
references.pmid: 16249345
references.citation: Immunity. 2012 Dec 14;37(6):1050-1060
references.pmid: 23177320
references.citation: J Biol Chem. 1999 Apr 16;274(16):11362-8
references.pmid: 10196228
references.citation: Oncogene. 2005 Feb 24;24(9):1552-62
references.pmid: 15674327
references.citation: Nat Immunol. 2012 Nov;13(11):1118-28
references.pmid: 23023392
references.citation: Cancer Discov. 2011 Jun;1(1):54-67
references.pmid: 22039576
references.citation: PLoS One. 2012;7(11):e46900
references.pmid: 23144792
references.citation: J Neurosci. 2011 Feb 23;31(8):2781-91
references.pmid: 21414900
references.citation: Ann Neurol. 2011 May;69(5):831-44
references.pmid: 21416488
references.citation: Science. 2010 Nov 5;330(6005):841-5
references.pmid: 20966214
references.citation: Brain Res. 1999 Sep 4;840(1-2):153-7
references.pmid: 10517963
references.citation: Nat Neurosci. 2011 Jul 31;14(9):1142-9
references.pmid: 21804537
references.citation: J Comp Neurol. 2005 Nov 14;492(2):178-92
references.pmid: 16196033
references.citation: J Immunol Methods. 1993 Mar 15;160(1):81-8
references.pmid: 7680699
references.citation: Brain Res. 1998 Aug 31;804(1):135-9
references.pmid: 9729335
references.citation: Glia. 2013 Jan;61(1):121-7
references.pmid: 22927325
references.citation: PLoS One. 2011;6(8):e22408
references.pmid: 21850226
references.citation: Nat Immunol. 2012 Jun 24;13(8):753-60
references.pmid: 22729249
references.citation: Cell Rep. 2013 Jul 25;4(2):385-401
references.pmid: 23850290
references.citation: Genesis. 2006 Jul;44(7):328-35
references.pmid: 16823860
references.citation: Science. 2013 Aug 9;341(6146):670-3
references.pmid: 23868921
references.citation: Cancer Res. 2014 Jan 1;74(1):153-161
references.pmid: 24247719
references.citation: Nat Neurosci. 2013 Mar;16(3):273-80
references.pmid: 23334579
references.citation: Nat Neurosci. 2014 Mar;17(3):400-6
references.pmid: 24487234
references.citation: Brain. 2009 Feb;132(Pt 2):288-95
references.pmid: 18567623
references.citation: Neuron. 2003 Jul 31;39(3):409-21
references.pmid: 12895417
references.citation: Mol Cancer Ther. 2006 Nov;5(11):2634-43
references.pmid: 17121910