Trends in Neurosciences
ReviewEmerging Roles for CSF-1 Receptor and its Ligands in the Nervous System
Section snippets
CSF-1R and CSF-1R Ligands and their Expression Patterns in Brain
CSF-1R is a class III receptor tyrosine kinase activated by two homodimeric glycoprotein ligands, CSF-1 [1] and IL-34) [2], that exhibit low primary sequence homology but share a short chain four α-helical bundle cytokine fold and interact with overlapping regions of the CSF-1R (reviewed in [3]). CSF-1 signals exclusively through the CSF-1R, while IL-34 interacts with at least one additional receptor, receptor protein tyrosine phosphatase-ζ (PTP-ζ), which is coexpressed with the CSF-1R on
Gross Abnormalities of Brain Development in CSF-1R- and CSF-1R Ligand-Deficient Mice
The relative importance of the CSF-1R and each of its ligands in development is reflected in the survival rates of mice bearing null mutations in each. C57BL/6 Il34−/− mice have a normal survival rate and their brains are grossly normal 7, 8, suggesting that IL-34 does not play an essential role in development. By contrast, Csf1op/op and Csf1r−/− mice exhibit reduced survival rates (Table 1). The brains of both Csf1op/op and Csf1r−/− mice are smaller in size with a greater mass. In addition,
The CSF-1R Directly Regulates Neural Progenitor Self-Renewal, Differentiation, and Survival
Given the expression of the CSF-1R on cells of the neuronal lineage, and the dysregulation of NPC survival, proliferation, and differentiation in Csf1r−/− brains, it was important to determine the functions of neuronal expression of CSF-1R [6]. In vitro studies utilizing purified, microglia-depleted NPCs revealed that either CSF-1 or IL-34 suppresses NPC self-renewal, but not their proliferation. Furthermore, in clonal differentiation assays, CSF-1 or IL-34 each increased the percentage of pure
CSF1R Mutations Cause Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ASLP)
Genome-wide linkage analysis and exome sequencing revealed that mutations in the CSF1R gene cause a rare, autosomal dominant, neurodegenerative disorder characterized by adult-onset dementia with motor impairments and epilepsy 40, 41. ALSP encompasses two similar diseases previously known as hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) [42] and familial pigmentary orthochromatic leukodystrophy (POLD) [43]. The median age of onset of ALSP is 42 ± 13 years (range 8–78) with
CSF-1R as a Possible Target in Neurological Disease
The CSF-1R and its ligands have also been shown to play important roles in demyelinating diseases, neurodegeneration including Alzheimer's disease (AD), and brain tumors (Figure 4B). Because increased levels of CSF-1, microgliosis, and microglial activation are found in many different CNS pathologies, it is important to understand the consequences of elevation of CSF-1R ligands. Mice engineered to overexpress CSF-1 in astrocytes exhibit increased microglial proliferation and decreased
Concluding Remarks
The discovery of high expression of the newly discovered CSF-1R ligand, IL-34, in brain [5], the drastic reduction of microglia in CSF-1R-deficient mice [22], together with earlier reports of neuronal expression of the CSF-1R 12, 62, prompted a detailed analysis of both CSF-1R and ligand expression and the effects of CSF-1R deficiency in the developing brain [6]. This study demonstrated direct CSF-1R regulation of the neuronal lineage and revealed complementary expression patterns of the CSF-1R
Acknowledgments
This work was supported by National Institutes of Health grants R01NS071571 and R01NS096144 (to M.F.M.) and R01NS091519 and PO1 CA100324 (to E.R.S.).
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