Dicer Deficiency Differentially Impacts Microglia of the Developing and Adult Brain

Immunity. 2017 Jun 20;46(6):1030-1044.e8. doi: 10.1016/j.immuni.2017.05.003.

Abstract

Microglia seed the embryonic neuro-epithelium, expand and actively sculpt neuronal circuits in the developing central nervous system, but eventually adopt relative quiescence and ramified morphology in the adult. Here, we probed the impact of post-transcriptional control by microRNAs (miRNAs) on microglial performance during development and adulthood by generating mice lacking microglial Dicer expression at these distinct stages. Conditional Dicer ablation in adult microglia revealed that miRNAs were required to limit microglial responses to challenge. After peripheral endotoxin exposure, Dicer-deficient microglia expressed more pro-inflammatory cytokines than wild-type microglia and thereby compromised hippocampal neuronal functions. In contrast, prenatal Dicer ablation resulted in spontaneous microglia activation and revealed a role for Dicer in DNA repair and preservation of genome integrity. Accordingly, Dicer deficiency rendered otherwise radio-resistant microglia sensitive to gamma irradiation. Collectively, the differential impact of the Dicer ablation on microglia of the developing and adult brain highlights the changes these cells undergo with time.

Keywords: DNA damage; LPS; LTP; development; dicer; endotoxin; hippocampus; long-term potentiation; microRNA; microglia; mutagenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cells, Cultured
  • DNA Repair
  • Female
  • Hippocampus / embryology
  • Hippocampus / growth & development
  • Hippocampus / metabolism*
  • Humans
  • Imaging, Three-Dimensional
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Microglia / physiology*
  • Motor Activity
  • Neuronal Plasticity
  • Neurons / physiology*
  • Ribonuclease III / genetics
  • Ribonuclease III / metabolism*

Substances

  • MicroRNAs
  • Ribonuclease III