Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations

Rocío Rojo, Anna Raper, Derya D. Ozdemir, Lucas Lefevre, Kathleen Grabert, Evi Wollscheid-Lengeling, Barry Bradford, Melanie Caruso, Iveta Gazova, Alejandra Sánchez, Zofia M. Lisowski, Joana Alves, Irene Molina-Gonzalez, Hayk Davtyan, Rebecca J. Lodge, James D. Glover, Robert Wallace, David A. D. Munro, Eyal David, Ido Amit, Véronique E. Miron, Josef Priller, Stephen J. Jenkins, Giles E. Hardingham, Mathew Blurton-Jones, Neil A. Mabbott, Kim M. Summers, Peter Hohenstein, David A. Hume () and Clare Pridans ()
Additional contact information
Rocío Rojo: University of Edinburgh, Easter Bush
Anna Raper: University of Edinburgh, Easter Bush
Derya D. Ozdemir: University of Edinburgh, Easter Bush
Lucas Lefevre: University of Edinburgh, Easter Bush
Kathleen Grabert: University of Edinburgh, Easter Bush
Evi Wollscheid-Lengeling: University of Edinburgh, Easter Bush
Barry Bradford: University of Edinburgh, Easter Bush
Melanie Caruso: University of Edinburgh, Easter Bush
Iveta Gazova: University of Edinburgh, Easter Bush
Alejandra Sánchez: University of Edinburgh, Easter Bush
Zofia M. Lisowski: University of Edinburgh, Easter Bush
Joana Alves: University of Edinburgh, Easter Bush
Irene Molina-Gonzalez: The Queen’s Medical Research Institute
Hayk Davtyan: University of California Irvine
Rebecca J. Lodge: The Queen’s Medical Research Institute
James D. Glover: University of Edinburgh, Easter Bush
Robert Wallace: University of Edinburgh
David A. D. Munro: The University of Edinburgh
Eyal David: Weizmann Institute of Science
Ido Amit: Weizmann Institute of Science
Véronique E. Miron: The Queen’s Medical Research Institute
Josef Priller: The University of Edinburgh
Stephen J. Jenkins: The Queen’s Medical Research Institute
Giles E. Hardingham: The University of Edinburgh
Mathew Blurton-Jones: University of California Irvine
Neil A. Mabbott: University of Edinburgh, Easter Bush
Kim M. Summers: Translational Research Institute
Peter Hohenstein: University of Edinburgh, Easter Bush
David A. Hume: Translational Research Institute
Clare Pridans: The Queen’s Medical Research Institute

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract The proliferation, differentiation and survival of mononuclear phagocytes depend on signals from the receptor for macrophage colony-stimulating factor, CSF1R. The mammalian Csf1r locus contains a highly conserved super-enhancer, the fms-intronic regulatory element (FIRE). Here we show that genomic deletion of FIRE in mice selectively impacts CSF1R expression and tissue macrophage development in specific tissues. Deletion of FIRE ablates macrophage development from murine embryonic stem cells. Csf1rΔFIRE/ΔFIRE mice lack macrophages in the embryo, brain microglia and resident macrophages in the skin, kidney, heart and peritoneum. The homeostasis of other macrophage populations and monocytes is unaffected, but monocytes and their progenitors in bone marrow lack surface CSF1R. Finally, Csf1rΔFIRE/ΔFIRE mice are healthy and fertile without the growth, neurological or developmental abnormalities reported in Csf1r−/− rodents. Csf1rΔFIRE/ΔFIRE mice thus provide a model to explore the homeostatic, physiological and immunological functions of tissue-specific macrophage populations in adult animals.

Date: 2019
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DOI: 10.1038/s41467-019-11053-8

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