Csf1r, the Colony-Stimulating Factor-1 Receptor, is a receptor tyrosine kinase. It is crucial for the differentiation and maintenance of most tissue-resident macrophages and bone-resorbing osteoclasts. Activation by endogenous cytokine ligation to its ectodomain triggers autophosphorylation of the intracellular tyrosine kinase domain, activating downstream pro-survival kinase cascades like PI3K, ERK1/2, and JNK [1].

In Csf1r-related leukoencephalopathy, more than 70 different mutations in the Csf1r gene have been identified. Haploinsufficiency of Csf1r in a patient with a frameshift mutation led to the establishment of a Csf1r haploinsufficient mouse model. These mice develop phenotypes consistent with human patients, suggesting a role of Csf1r in neurodegeneration [2]. Deletion of the fms-intronic regulatory element (FIRE), a super-enhancer of the Csf1r locus in mice, selectively impacts Csf1r expression and tissue macrophage development. Csf1rΔFIRE/ΔFIRE mice lack macrophages in specific tissues like the embryo, brain microglia, and resident macrophages in certain organs, while other macrophage populations are unaffected [3].

In conclusion, Csf1r is essential for the development and function of macrophages and osteoclasts. Mouse models with Csf1r mutations or deletions have been instrumental in understanding its role in neurodegenerative diseases like Csf1r-related leukoencephalopathy and in revealing the tissue-specific importance of Csf1r in macrophage development.