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

Simone Brioschi; Julia A Belk; Vincent Peng; Martina Molgora; Patrick Fernandes Rodrigues; Khai M Nguyen; Shoutang Wang; Siling Du; Wei-Le Wang; Gary E Grajales-Reyes; Jennifer M Ponce; Carla M Yuede; Qingyun Li; John M Baer; David G DeNardo; Susan Gilfillan; Marina Cella; Ansuman T Satpathy; Marco Colonna

doi:10.1016/j.immuni.2023.01.028

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.

Authors

Simone Brioschi¹, Julia A Belk², Vincent Peng³, Martina Molgora³, Patrick Fernandes Rodrigues³, Khai M Nguyen³, Shoutang Wang³, Siling Du³, Wei-Le Wang³, Gary E Grajales-Reyes³, Jennifer M Ponce⁴, Carla M Yuede⁵, Qingyun Li⁶, John M Baer⁷, David G DeNardo⁸, Susan Gilfillan³, Marina Cella³, Ansuman T Satpathy⁹, Marco Colonna¹⁰

Affiliations

¹ Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA. Electronic address: s.brioschi@wustl.edu.
² Department of Computer Science, Stanford University, Stanford, CA, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
³ Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA.
⁴ McDonnell Genome Institute, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA.
⁵ Department of Psychiatry, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA.
⁶ Department of Neuroscience, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA; Department of Genetics, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA.
⁷ Department of Medicine, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA.
⁸ Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA; Department of Medicine, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA; Siteman Cancer Center, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA.
⁹ Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Pathology, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University, Stanford, CA, USA.
¹⁰ Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA. Electronic address: mcolonna@wustl.edu.

PMID: 36791722
PMCID: PMC10175109 (available on 2024-05-09)
DOI: 10.1016/j.immuni.2023.01.028

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding