Wild type bone marrow-derived microglia-like cells mitigate strain-dependent neuropathology in Csf1r mutant mice.

Germ-line deletion of a conserved enhancer (FIRE) in the mouse Csf1r locus (Fireko) causes congenital absence of microglia. The current study analyses the effect of microglial deficiency on gene expression during postnatal brain development and defines the effect of mouse genetic background on the Fireko phenotype and age-dependent pathology. In total RNA-seq data from multiple brain regions of juvenile wild-type and Fireko mice, transcripts associated with endosome/lysosome function and other transcripts strongly enriched in isolated microglia were not affected indicating compensatory expression by other cell types. The Fireko mutation on a C57BL/6J background led to perinatal lethality and hydrocephalus (HC) in surviving pups that was overcome in F2 intercross with CBA or BALB/c. The absence of microglia in Fireko mice did not affect motor activity, behaviour, or myelination but aged mice developed astrocytosis and subsequent severe calcification in the thalamus. Intraperitoneal transfer of WT bone marrow cells (BMT) repopulated the brain with microglia-like cells that expressed damage-associated transcripts and proteins. BMT prevented calcification in the thalamus but neither increased nor decreased markers of astrocyte or oligodendrocyte activation. The results suggest that the damage-associated microglial phenotype is a protective response to injury rather than a cause of neuropathology.