A Cre-deleter specific for embryo-derived brain macrophages reveals distinct features of microglia and border macrophages

Immunity. 2023 May 9;56(5):1027-1045.e8. doi: 10.1016/j.immuni.2023.01.028. Epub 2023 Feb 14.

Abstract

Genetic tools to target microglia specifically and efficiently from the early stages of embryonic development are lacking. We generated a constitutive Cre line controlled by the microglia signature gene Crybb1 that produced nearly complete recombination in embryonic brain macrophages (microglia and border-associated macrophages [BAMs]) by the perinatal period, with limited recombination in peripheral myeloid cells. Using this tool in combination with Flt3-Cre lineage tracer, single-cell RNA-sequencing analysis, and confocal imaging, we resolved embryonic-derived versus monocyte-derived BAMs in the mouse cortex. Deletion of the transcription factor SMAD4 in microglia and embryonic-derived BAMs using Crybb1-Cre caused a developmental arrest of microglia, which instead acquired a BAM specification signature. By contrast, the development of genuine BAMs remained unaffected. Our results reveal that SMAD4 drives a transcriptional and epigenetic program that is indispensable for the commitment of brain macrophages to the microglia fate and highlight Crybb1-Cre as a tool for targeting embryonic brain macrophages.

Keywords: BAMs; SMAD4; fate-mapping; macrophages ontogeny; microglia.

Publication types

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

MeSH terms

  • Animals
  • Brain / metabolism
  • Integrases / genetics
  • Integrases / metabolism
  • Macrophages* / metabolism
  • Mice
  • Microglia* / metabolism

Substances

  • Cre recombinase
  • Integrases