8 November 2019

Tjakko van Ham

Neuroscience Symposium
Huitinga Group

The Neuroscience Symposia are organized weekly by the Netherlands Institute for Neuroscience. The presentations are given by researchers from the institute or by guest speakers. The title and content of the symposium is usually made known in the week prior to the presentation.

Colloquium room – Netherlands Institute for Neuroscience

4:00 PM – Genetics of microglia development and function: From zebrafish to human disease
5:00 PM – Discussion and drinks

Microglia are brain-resident macrophages with trophic and phagocytic functions, but it is unclear what their contribution to normal brain development and homeostasis is. Dominant loss-of-function mutations in a key microglia regulator, colony-stimulating factor 1 receptor (CSF1R), cause adultonset 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. 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 and that microglia depletion may contribute to loss of white matter. We also recently described patients with pediatric-onset leukodystrophy and bi-allelic mutations in CSF1R, showing pathological features overlapping with ALSP, but much more severe. We are currently investigating how loss of microglia affects brain development and homeostasis, and whether peripheral loss of macrophages would also affect the brain, and thereby would also play a role in disease. Therefore we take advantage of the unique experimental features of zebrafish, including their transparency in larval stages, genetic manipulability and conserved genetics and cell biology, in combination with analyses of post-mortem patient tissues.