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

Rocío Rojo1,2, Anna Raper1, Derya D Ozdemir1

  • 1The Roslin Institute & Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK.

Nature Communications
|July 21, 2019
PubMed

Insights

Deleting the fms-intronic regulatory element (FIRE) in mice selectively removes tissue macrophages without affecting overall health. This creates a model to study specific macrophage functions in adult animals.

Area of Science:

  • Immunology
  • Developmental Biology
  • Genetics

Background:

  • Mononuclear phagocyte development relies on macrophage colony-stimulating factor receptor (CSF1R) signaling.
  • The mammalian Csf1r gene locus features a conserved super-enhancer element known as FIRE.
  • Understanding the role of specific regulatory elements in gene expression is crucial for cell development.

Purpose of the Study:

  • To investigate the function of the FIRE element in regulating CSF1R expression and macrophage development.
  • To determine the impact of FIRE deletion on tissue-specific macrophage populations.
  • To establish a novel mouse model for studying tissue-specific macrophage functions.

Main Methods:

  • Genomic deletion of the FIRE element in mouse embryonic stem cells and whole animals (Csf1rΔFIRE/ΔFIRE mice).
  • Analysis of CSF1R expression in various tissues and cell types.
  • Assessment of macrophage populations in embryonic and adult Csf1rΔFIRE/ΔFIRE mice.
  • Evaluation of overall health, fertility, and development in Csf1rΔFIRE/ΔFIRE mice.

Main Results:

  • Genomic deletion of FIRE selectively impaired CSF1R expression.
  • FIRE deletion led to the ablation of macrophage development from embryonic stem cells.
  • Csf1rΔFIRE/ΔFIRE mice exhibited a complete absence of embryonic macrophages, brain microglia, and resident macrophages in multiple organs.
  • Monocyte homeostasis and other macrophage populations remained largely unaffected.
  • Monocytes and their progenitors in bone marrow lacked surface CSF1R expression.
  • Csf1rΔFIRE/ΔFIRE mice were healthy and fertile, lacking the severe abnormalities seen in Csf1r-/- rodents.

Conclusions:

  • The FIRE element is essential for CSF1R expression and the development of specific tissue macrophage populations.
  • FIRE deletion provides a unique model to study the functions of tissue-resident macrophages in vivo without systemic complications.
  • This research highlights the critical role of enhancers in orchestrating cell-type-specific gene regulation during development.

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