Cx3Cr1-Cre induction leads to microglial activation and IFN-1 signaling caused by DNA damage in early postnatal brain

Cell Rep. 2022 Jan 18;38(3):110252. doi: 10.1016/j.celrep.2021.110252.

Abstract

Cx3cr1CreER-driven Cre recombinase (Cre) is a widely used genetic tool for enabling gene manipulation in microglia and macrophages. However, an in-depth analysis of the possible detrimental effects of Cre activity in microglia, surprisingly, remains missing. Here, we demonstrate an age-dependent sensitivity of microglia to Cx3cr1-Cre toxicity, wherein Cre induction, specifically in early postnatal microglia, is detrimental to microglial development, proliferation, and function. Tamoxifen (TAM)-induced Cre activity leads to microglial activation, type 1 interferon (IFN-1) signaling, and increased phagocytosis, causing aberrant synaptic pruning during the early postnatal period and anxious behavior at later age. The detrimental effects of Cre induction are caused by DNA-damage-induced toxicity in microglia and are limited to the early postnatal period, showing no detrimental effects in adult microglia. Thus, our study reveals an age-dependent vulnerability of microglia to Cre activity, thereby highlighting age dependency of Cre action, which could be especially applicable in the broader context of environment-responsive cell types.

Keywords: Cre toxicity; DNA damage; IFN-1 signaling; early postnatal microglia; synaptic pruning.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified / metabolism*
  • Animals, Newborn
  • Brain / metabolism
  • Brain / pathology*
  • CX3C Chemokine Receptor 1*
  • DNA Damage
  • Genetic Techniques / adverse effects
  • Integrases*
  • Interferon Type I / metabolism*
  • Mice
  • Microglia / metabolism
  • Microglia / pathology*

Substances

  • CX3C Chemokine Receptor 1
  • Cx3cr1 protein, mouse
  • Interferon Type I
  • Cre recombinase
  • Integrases