Review
Emerging Roles for CSF-1 Receptor and its Ligands in the Nervous System

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CSF-1R is a receptor tyrosine kinase with two cognate ligands, CSF-1 and IL-34, that are expressed in largely non-overlapping areas of the CNS and that regulate microglial proliferation, and survival.

The CSF-1R is also expressed in neural progenitor cells and regulates their survival, proliferation and neuronal differentiation.

Upregulation of CSF-1R expression in injured neurons promotes survival.

Mutations in the CSF1R gene lead to an autosomal dominant, neurodegenerative disorder known as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

The Csf1r+/− mouse is a validated model for testing therapeutic strategies for ALSP.

CSF-1R ligands and inhibitors are potential modulators of several neurological diseases including Alzheimer's disease, globoid cell leukodystrophy (Krabbe's disease), Charcot–Marie–Tooth disease, multiple sclerosis, and glioma.

The colony-stimulating factor-1 receptor (CSF-1R) kinase regulates tissue macrophage homeostasis, osteoclastogenesis, and Paneth cell development. However, recent studies in mice have revealed that CSF-1R signaling directly controls the development and maintenance of microglia, and cell autonomously regulates neuronal differentiation and survival. While the CSF-1R-cognate ligands, CSF-1 and interleukin-34 (IL-34) compete for binding to the CSF-1R, they are expressed in a largely non-overlapping manner by mature neurons. The recent identification of a dominantly inherited, adult-onset, progressive dementia associated with inactivating mutations in the CSF-1R highlights the importance of CSF-1R signaling in the brain. We review the roles of the CSF-1R and its ligands in microglial and neural development and function, and their relevance to our understanding of neurodegenerative disease.

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.).

References (109)

  • C.N. Parkhurst

    Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor

    Cell

    (2013)
  • J. Bruttger

    Genetic cell ablation reveals clusters of local self-renewing microglia in the mammalian central nervous system

    Immunity

    (2015)
  • V. Chitu

    PSTPIP2 deficiency in mice causes osteopenia and increased differentiation of multipotent myeloid precursors into osteoclasts

    Blood

    (2012)
  • M. Hiyoshi

    M-CSF receptor mutations in hereditary diffuse leukoencephalopathy with spheroids impair not only kinase activity but also surface expression

    Biochem. Biophys. Res. Commun.

    (2013)
  • J. Paloneva

    Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype

    Am. J. Hum. Genet.

    (2002)
  • C.I. Caescu

    Colony stimulating factor-1 receptor signaling networks inhibit mouse macrophage inflammatory responses by induction of microRNA-21

    Blood

    (2015)
  • Y. Uemura

    The selective M-CSF receptor tyrosine kinase inhibitor Ki20227 suppresses experimental autoimmune encephalomyelitis

    J. Neuroimmunol.

    (2008)
  • M.R. Walton et al.

    Is CREB a key to neuronal survival?

    Trends Neurosci.

    (2000)
  • H. Lee

    Defective self-renewal and differentiation of GBA-deficient neural stem cells can be restored by macrophage colony-stimulating factor

    Mol. Cells

    (2015)
  • H. Akiyama

    Inflammation and Alzheimer's disease

    Neurobiol. Aging

    (2000)
  • G.M. Murphy

    Expression of macrophage colony-stimulating factor receptor is increased in the AbetaPP(V717F) transgenic mouse model of Alzheimer's disease

    Am. J. Pathol.

    (2000)
  • T. Mizuno

    Interleukin-34 selectively enhances the neuroprotective effects of microglia to attenuate oligomeric amyloid-beta neurotoxicity

    Am. J. Pathol.

    (2011)
  • S. Nandi

    Receptor-type protein-tyrosine phosphatase zeta is a functional receptor for interleukin-34

    J. Biol. Chem.

    (2013)
  • P. Squarzoni

    Microglia modulate wiring of the embryonic forebrain

    Cell Rep.

    (2014)
  • Y. Wu

    Microglia: dynamic mediators of synapse development and plasticity

    Trends Immunol.

    (2015)
  • M. Nikodemova

    Microglial numbers attain adult levels after undergoing a rapid decrease in cell number in the third postnatal week

    J. Neuroimmunol.

    (2015)
  • J.L. Marin-Teva

    Microglia promote the death of developing Purkinje cells

    Neuron

    (2004)
  • A. Sierra

    Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis

    Cell Stem Cell

    (2010)
  • E. Peles

    Multi-ligand interactions with receptor-like protein tyrosine phosphatase beta: implications for intercellular signaling

    Trends Biochem. Sci.

    (1998)
  • H. Lin

    Discovery of a cytokine and its receptor by functional screening of the extracellular proteome

    Science

    (2008)
  • E.R. Stanley et al.

    CSF-1 receptor signaling in myeloid cells

    Cold Spring Harb. Perspect. Biol.

    (2014)
  • A. von Holst

    The unique 473HD-chondroitinsulfate epitope is expressed by radial glia and involved in neural precursor cell proliferation

    J. Neurosci.

    (2006)
  • S. Wei

    Functional overlap but differential expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated regulation of myeloid cells

    J. Leukoc. Biol.

    (2010)
  • Y. Wang

    IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia

    Nat. Immunol.

    (2012)
  • G. Raivich

    Regulation of MCSF receptors on microglia in the normal and injured mouse central nervous system: a quantitative immunofluorescence study using confocal laser microscopy

    J. Comp. Neurol.

    (1998)
  • Y. Wang

    Expression of colony stimulating factor-1 receptor (CSF-1R) by CNS neurons in mice

    J. Neurosci. Res.

    (1999)
  • S. Murase et al.

    Expression pattern and neurotrophic role of the c-fms proto-oncogene M-CSF receptor in rodent Purkinje cells

    J. Neurosci.

    (1998)
  • J. Luo

    Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival

    J. Exp. Med.

    (2013)
  • A. Sierra

    Microglia derived from aging mice exhibit an altered inflammatory profile

    Glia

    (2007)
  • B. Erblich

    Absence of colony stimulation factor-1 receptor results in loss of microglia, disrupted brain development and olfactory deficits

    PLoS ONE

    (2011)
  • A. Olmos-Alonso

    Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology

    Brain

    (2016)
  • S.H. Burnett

    Conditional macrophage ablation in transgenic mice expressing a Fas-based suicide gene

    J. Leukoc. Biol.

    (2004)
  • Y. Wang

    CSF-1 stimulated multiubiquitination of the CSF-1 receptor and of Cbl follows their tyrosine phosphorylation and association with other signaling proteins

    J. Cell. Biochem.

    (1999)
  • F. Ginhoux

    Fate mapping analysis reveals that adult microglia derive from primitive macrophages

    Science

    (2010)
  • M. Hristova

    Activation and deactivation of periventricular white matter phagocytes during postnatal mouse development

    Glia

    (2010)
  • G. Miyoshi et al.

    GABAergic interneuron lineages selectively sort into specific cortical layers during early postnatal development

    Cereb. Cortex

    (2011)
  • G. Hoeffel

    Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages

    J. Exp. Med.

    (2012)
  • A. Sasaki

    Effects of macrophage-colony-stimulating factor deficiency on the maturation of microglia and brain macrophages and on their expression of scavenger receptor

    Neuropathology

    (2000)
  • A. Lelli

    The NADPH oxidase Nox2 regulates VEGFR1/CSF-1R-mediated microglial chemotaxis and promotes early postnatal infiltration of phagocytes in the subventricular zone of the mouse cerebral cortex

    Glia

    (2013)
  • Y. Kondo et al.

    Selective reduction in microglia density and function in the white matter of colony-stimulating factor-1-deficient mice

    J. Neurosci. Res.

    (2009)
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