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Colony-Stimulating Factor 1 Receptor (CSF1R) Regulates Microglia Density and Distribution, but Not Microglia

Nynke Oosterhof1, Laura E Kuil1, Herma C van der Linde1

  • 1Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.

Cell Reports
|August 2, 2018
PubMed

Insights

Colony-stimulating factor 1 receptor (CSF1R) mutations disrupt microglia density, leading to their loss in the brain. This microglia depletion may contribute to adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

Area of Science:

  • Neuroscience
  • Immunology
  • Genetics

Background:

  • Microglia, the brain's resident macrophages, are crucial for neural health.
  • Mutations in colony-stimulating factor 1 receptor (CSF1R) cause adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a white matter disorder.
  • The precise impact of CSF1R mutations on microglia remains poorly understood.

Purpose of the Study:

  • To investigate CSF1R-dependent changes in microglia.
  • To elucidate the role of CSF1R in regulating microglia density and distribution.
  • To explore the link between microglia loss and ALSP pathogenesis.

Main Methods:

  • Generation of an allelic series of csf1r mutants in zebrafish.
  • Analysis of microglia density, distribution, and gene expression in zebrafish mutants.
  • Examination of microglia numbers in postmortem brain tissue from ALSP patients.

Main Results:

  • csf1r mutations in zebrafish resulted in abnormal microglia density, distribution, and regional depletion.
  • Remaining microglia in mutants maintained a normal gene expression signature.
  • ALSP patients exhibited reduced microglia numbers and widespread depletion, even in unaffected brain regions.

Conclusions:

  • CSF1R plays a critical role in regulating microglia density and maintaining their numbers within the brain.
  • Loss of microglia, potentially driven by CSF1R dysfunction, may be an early event contributing to ALSP.
  • Microglia depletion occurs independently of overt pathology in both zebrafish models and human ALSP.
Keywords:
ALSPCSF1RHDLScolony-stimulating factor 1 receptorleukodystrophymacrophagesmicroglianeurodegenerationtranscriptomicszebrafish

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