PUBLICATION
Colony-Stimulating Factor 1 Receptor (CSF1R) Regulates Microglia Density and Distribution, but Not Microglia Differentiation In Vivo
- Authors
- Oosterhof, N., Kuil, L.E., van der Linde, H.C., Burm, S.M., Berdowski, W., van Ijcken, W.F.J., van Swieten, J.C., Hol, E.M., Verheijen, M.H.G., van Ham, T.J.
- ID
- ZDB-PUB-180802-9
- Date
- 2018
- Source
- Cell Reports 24: 1203-1217.e6 (Journal)
- Registered Authors
- Kuil, Laura, van der Linde, Herma, van Ham, Tjakko
- Keywords
- ALSP, CSF1R, HDLS, colony-stimulating factor 1 receptor, leukodystrophy, macrophages, microglia, neurodegeneration, transcriptomics, zebrafish
- MeSH Terms
-
- Animals
- Cell Differentiation*
- Humans
- Leukoencephalopathies/metabolism*
- Leukoencephalopathies/pathology
- Microglia/cytology
- Microglia/metabolism*
- Mutation
- Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/genetics
- Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism*
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 30067976 Full text @ Cell Rep.
Citation
Oosterhof, N., Kuil, L.E., van der Linde, H.C., Burm, S.M., Berdowski, W., van Ijcken, W.F.J., van Swieten, J.C., Hol, E.M., Verheijen, M.H.G., van Ham, T.J. (2018) Colony-Stimulating Factor 1 Receptor (CSF1R) Regulates Microglia Density and Distribution, but Not Microglia Differentiation In Vivo. Cell Reports. 24:1203-1217.e6.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping