Genetics of Tissue Macrophage Development and Function : From zebrafish to human disease

In this thesis we aimed to gain insight in the mechanisms and genetics regulating the embryonic development of macrophages, particularly microglia, and their role in disease. We therefore designed a reverse genetic screen to identify genes important for early microglia development in zebrafish larvae. In this screen, we identified Il34 as regulator of microglia development by attracting precursors towards to brain to form microglia. To further study the role of Csf1r-signaling in macrophage development in vivo, we generated zebrafish lacking both copies of the Il34 receptor, Csf1r. We studied the role of Csf1r during embryonic and larval macrophage development and in adulthood. Csf1r mainly regulates macrophage proliferation, distribution and density whereas differentiation to core-macrophages is Csf1r independent. Hereby, we gained insight in the role of microglia in the rare neurodegenerative disorder ALSP, caused by heterozygous mutations in CSF1R, were we also showed reduced and aberrant distributed microglia. In addition, we described a human patient with homozygous loss of function mutations in CSF1R that lacks microglia. We used the zebrafish to study how the lack of microglia affects brain development, providing an indication for the mechanism underlying the absence of major white matter tracts in the patient. In addition, the microglia signature gene hexb, which causes Sandhoff disease, was studied by mutating this gene in zebrafish. We discovered pathologies both in microglia and radial glia during early development of hexb mutant larvae, suggesting a role for multiple glia in Sandhoff disease onset.

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