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Cell Rep. 2018 Jul 31;24(5):1203-1217.e6. doi: 10.1016/j.celrep.2018.06.113.

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

Author information

1
Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
2
Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
3
Center for Biomics, Erasmus MC, University Medical Center Rotterdam, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
4
Department of Neurology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Clinical Genetics, VU Medical Center, Amsterdam, the Netherlands.
5
Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Department of Neuroimmunology, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands.
6
Department of Molecular and Cellular Neurobiology, CNCR, Amsterdam Neuroscience, VU University, Amsterdam, the Netherlands.
7
Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands. Electronic address: t.vanham@erasmusmc.nl.

Abstract

Microglia are brain-resident macrophages with trophic and phagocytic functions. Dominant loss-of-function mutations in a key microglia regulator, colony-stimulating factor 1 receptor (CSF1R), cause adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a progressive white matter disorder. Because it remains unclear precisely how CSF1R mutations affect microglia, we generated an allelic series of csf1r mutants in zebrafish to identify csf1r-dependent microglia changes. We found that csf1r mutations led to aberrant microglia density and distribution and regional loss of microglia. The remaining microglia still had a microglia-specific gene expression signature, indicating that they had differentiated normally. Strikingly, we also observed lower microglia numbers and widespread microglia depletion in postmortem brain tissue of ALSP patients. Both in zebrafish and in human disease, local microglia loss also presented in regions without obvious pathology. Together, this implies that CSF1R mainly regulates microglia density and that early loss of microglia may contribute to ALSP pathogenesis.

KEYWORDS:

ALSP; CSF1R; HDLS; colony-stimulating factor 1 receptor; leukodystrophy; macrophages; microglia; neurodegeneration; transcriptomics; zebrafish

PMID:
30067976
DOI:
10.1016/j.celrep.2018.06.113
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