Pleiotropic Impacts of Macrophage and Microglial Deficiency on Development in Rats with Targeted Mutation of the Csf1r Locus

Abstract

We have produced Csf1r-deficient rats by homologous recombination in embryonic stem cells. Consistent with the role of Csf1r in macrophage differentiation, there was a loss of peripheral blood monocytes, microglia in the brain, epidermal Langerhans cells, splenic marginal zone macrophages, bone-associated macrophages and osteoclasts, and peritoneal macrophages. Macrophages of splenic red pulp, liver, lung, and gut were less affected. The pleiotropic impacts of the loss of macrophages on development of multiple organ systems in rats were distinct from those reported in mice. Csf1r−/− rats survived well into adulthood with postnatal growth retardation, distinct skeletal and bone marrow abnormalities, infertility, and loss of visceral adipose tissue. Gene expression analysis in spleen revealed selective loss of transcripts associated with the marginal zone and, in brain regions, the loss of known and candidate novel microglia-associated transcripts. Despite the complete absence of microglia, there was little overt phenotype in brain, aside from reduced myelination and increased expression of dopamine receptor-associated transcripts in striatum. The results highlight the redundant and nonredundant functions of CSF1R signaling and of macrophages in development, organogenesis, and homeostasis.

Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations

“…Notably, the level of both CSF1R and CSF1 binding is reduced by around 50% in the heterozygotes (Fig. 3c, d), which is consistent with a lack of dosage compensation at the mRNA level also reported in Csf1r -deficient mice and rats 4,5 .

Fig. 3FIRE deletion reduced functional CSF1R expression in blood.

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“…The development of normal sexual maturity is compromised in both male and female Csf1 op/op mice 22,23 and in Csf1r −/− rats 5 . By contrast, the Csf1r ΔFIRE/ΔFIRE mice reach sexual maturity and are fertile.…”

“…reptiles, birds, and humans) 2,3 . Deletion of the Csf1r locus in the mouse or rat germ line produces a global deficiency in most tissue macrophage populations 4,5 . Mutant animals are osteopetrotic (associated with loss of osteoclasts) and exhibit severe postnatal growth retardation and multiple pleiotropic impacts on development.…”

Differential microglia and macrophage profiles in human IDH-mutant and -wild type glioblastoma

“…Furthermore, FCER1G and TYROBP have been identified as two of three hub genes in a protein-protein interaction network positively correlated with the progression of clear cell renal cell carcinoma [44]. FCER1G and TYROBP encode for ITAM-containing adaptor proteins which may play major roles in CSF1R signaling [45], a receptor crucial to microglia and macrophage homeostasis and differentiation [46]. Similarly, C1QA and C1QB are involved in regulating IFNγ signaling [47], a pathway crucial to pro-inflammatory cytokine secretion in microglia and macrophages.…”

Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease

“…In numerous preclinical models of neurodegenerative disease, and in post-mortem brain samples from AD patients, an increase in microglia number and their proliferation rate has been observed (Perry et al, 2010;Gómez-Nicola et al, 2013;Walker et al, 2017). This proliferative activity is regulated by the tyrosine kinase, CSF1R; indeed, CSF1R-deficient mice and rats have no microglia (Ginhoux et al, 2010;Erblich et al, 2011;Gómez-Nicola et al, 2013;Pridans et al, 2018). Furthermore, CSF1R itself is upregulated in preclinical neurodegeneration models and human post-mortem samples (Akiyama et al, 1994;Murphy et al, 2000).…”