Colony Stimulating Factor-1 (CSF-1) is the primary regulator of the survival, proliferation and differentiation of mononuclear phagocytes. All of the effects of CSF-1 are mediated by the high affinity CSF-1 receptor (CSF-1R), a protein tyrosine kinase encoded by the c-fms proto-oncogene. Previous studies have shown that the phenotype of CSF-1 receptor-deficient (Csf1r−/−) mice is more severe than the phenotype of CSF-1-deficient (Csf1op/op) mice. Csf1r−/− mice have a more severe osteopetrosis, fewer osteoclasts, lower survival and fewer tissue macrophages and these differences are more pronounced on single strain backgrounds. This led us to speculate that there may be another ligand for the CSF-1R (

Dai et al.,
Dai et al.,
J. Bone Min. Res.
). This was recently confirmed by the discovery of the novel cytokine Interleukin 34 (IL-34), which specifically binds to the CSF-1R (
Lin et al.,
). Like the secreted glycoprotein isoform of CSF-1 (sgpCSF-1), with which it shares no sequence similarity, IL-34 is a dimeric glycoprotein. Like CSF-1, it is broadly expressed in embryonic and adult tissues and it stimulates macrophage colony formation. We hypothesized that there is an incomplete overlap in the expression pattern of IL-34 and CSF-1 in the various cell types in which they are expressed and/or that expression of IL-34 and CSF-1 are differently regulated during mouse development. In transgenes, the CSF-1 promoter and first intron drives normal tissue specific and developmental expression of CSF-1 and such transgenes expressing sgpCSF-1 on the Csf1 op/op background partially rescue defects associated with CSF-1 deficiency (
Nandi et al.,
). Thus one test of this hypothesis is to determine whether expression of IL-34 under the control of the same driver rescues those aspects of the CSF-1-deficient phenotype rescued by sgpCSF-1. We therefore generated the transgenic lines in which the expression of mouse IL-34 is under the control of CSF-1 promoter and first intron. One of these transgenic mouse lines rescued the Csf1op/op deficiences, like similarly-driven sgpCSF-1. These studies indicate that IL-34 can function like sgpCSF-1 in vivo when expressed in a CSF-1-dependent manner.

Disclosures: No relevant conflicts of interest to declare.

[Supported in part by NIH grant CA 32551 (ERS)].

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