Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain

Neuron. 2014 Apr 16;82(2):380-97. doi: 10.1016/j.neuron.2014.02.040.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult Stem Cells / drug effects
  • Adult Stem Cells / physiology*
  • Animals
  • Animals, Newborn
  • Brain / cytology
  • Brain / drug effects
  • Brain / metabolism*
  • Cell Death / drug effects
  • Cell Proliferation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Lipopolysaccharides / pharmacology
  • Macrophage Colony-Stimulating Factor / antagonists & inhibitors
  • Macrophage Colony-Stimulating Factor / genetics
  • Macrophage Colony-Stimulating Factor / metabolism
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / metabolism*
  • Nerve Tissue Proteins / metabolism
  • Receptor, Macrophage Colony-Stimulating Factor / genetics
  • Receptor, Macrophage Colony-Stimulating Factor / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Time Factors

Substances

  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Nerve Tissue Proteins
  • Macrophage Colony-Stimulating Factor
  • Receptor, Macrophage Colony-Stimulating Factor