CSF1R — Colony Stimulating Factor 1 Receptor
<table class="infobox infobox-gene">
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<th class="infobox-header" colspan="2">CSF1R — Colony Stimulating Factor 1 Receptor</th>
</tr>
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<td class="label">Symbol</td>
<td><strong>CSF1R</strong></td>
</tr>
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<td class="label">Full Name</td>
<td>Colony Stimulating Factor 1 Receptor</td>
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<td class="label">Chromosome</td>
<td>5q32</td>
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<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/1436" target="_blank">1436</a></td>
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<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000182578" target="_blank">ENSG00000182578</a></td>
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<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/164770" target="_blank">164770</a></td>
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<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P07333" target="_blank">P07333</a></td>
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<td class="label">Diseases</td>
<td>ALSP, HDLS</td>
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<td class="label">Expression</td>
<td>[Microglia](/cell-types/microglia), Macrophages, Osteoclasts, Placenta</td>
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<th class="infobox-subheader" colspan="2">Key Mutations</th>
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<td colspan="2" style="font-size:0.85em">Kinase domain mutations (most common)<br>p.Ile794Thr<br>p.Ala781Val<br>p.His888Arg<br>>70 mutations reported</td>
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<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">CANCER</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a></td>
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<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">164 edges</a></td>
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</table>
CSF1R — Colony Stimulating Factor 1 Receptor
Pathway Diagram
Mermaid diagram (expand to render)
Introduction
Csf1R — Colony Stimulating Factor 1 Receptor is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Overview
CSF1R (Colony Stimulating Factor 1 Receptor, also known as CD115) is a receptor tyrosine kinase encoded on chromosome 5q32 that plays a pivotal role in the survival, proliferation, differentiation, and function of mononuclear phagocytes[@stanley2014]. CSF1R is the primary driver of microglial development and maintenance, making it a critical gene in neurodegenerative disease research. Heterozygous pathogenic variants in CSF1R cause adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP/HDSL), a hereditary progressive white matter disorder. The gene is catalogued as NCBI Gene ID [1436](https://www.ncbi.nlm.nih.gov/gene/1436) and OMIM [164770](https://omim.org/entry/164770).
Function
CSF1R Signaling Pathway
CSF1R is activated by three ligands: CSF1 (M-CSF), IL-34, and CSF1V (viral CSF1)[@lin2018]. Upon ligand binding, CSF1R undergoes:
Dimerization: Two CSF1R molecules pair in the membrane
Autophosphorylation: Intracellular tyrosine residues are phosphorylated
Docking site creation: Phospho-tyrosines recruit downstream signaling proteins
Signal transduction: Multiple pathways are activatedDownstream Signaling Pathways
- PI3K/AKT pathway: Cell survival, proliferation, metabolism
- MAPK/ERK pathway: Cell growth, differentiation
- STAT3 pathway: Transcriptional regulation, inflammation
- PLCγ pathway: Calcium signaling, cytoskeletal reorganization
- [NF-κB](/entities/nf-kb) pathway: Pro-inflammatory gene expression
Role in Microglia
CSF1R is essentially the master regulator of microglia[@ginhoux2010]:
- Development: CSF1R signaling is absolutely required for microglial progenitor survival and proliferation during embryonic development
- Maintenance: Adult microglia depend on CSF1R signaling for homeostasis
- Activation: CSF1R modulates microglial activation states, influencing the neurotoxic vs. neuroprotective phenotype
- Repopulation: After depletion (e.g., from radiation), microglia repopulate from resident progenitors in a CSF1R-dependent manner
Brain Expression
- [Microglia](/cell-types/microglia): Highest expression in brain; CSF1R is the defining marker of microglia
- Macrophages: Tissue-resident and infiltrating macrophages
- Osteoclasts: Bone-resorbing cells (in bone marrow)
- Placenta: Hofbauer cells (placental macrophages)
- Liver: Kupffer cells (liver macrophages)
Expression data is available from the [Allen Human Brain Atlas](https://human.brain-map.org/microarray/search/show?search_term=CSF1R).
Disease Associations
Adult-Onset Leukoencephalopathy with Spheroids and Pigmented Glia (ALSP)
ALSP (also known as Hereditary Diffuse Leukoencephalopathy with Spheroids, HDLS) is an autosomal dominant disorder caused by heterozygous pathogenic variants in CSF1R[@rademakers2012].
Clinical Features
- Age of onset: Typically 30-50 years (can range from 18-78)
- Progressive neurological decline:
- Cognitive impairment (subcortical dementia, executive dysfunction)
- Personality changes (apathy, disinhibition)
- Psychiatric symptoms (depression, psychosis)
- Motor symptoms (parkinsonism, gait disturbance, spasticity)
- Seizures
- Neuroimaging:
- Confluent white matter hyperintensities (T2/FLAIR)
- Posterior predominance (occipital lobes)
- Corpus callosum thinning
- Cortical atrophy (later stages)
Pathophysiology
CSF1R mutations cause loss of function in the receptor tyrosine kinase[@konno2018]:
- Haploinsufficiency: Mutant allele produces insufficient functional protein
- Dominant-negative effect: Mutant protein may interfere with wild-type signaling
- Microglial dysfunction: Impaired microglial survival, activation, and homeostasis
- White matter degeneration: Axonal spheroids, myelin loss, pigmented glia
Alzheimer's Disease
CSF1R is a major therapeutic target in AD due to its role in microglial biology[@wang2017]:
- Microglial activation: CSF1R drives disease-associated microglia (DAM) formation
- Amyloid response: [Microglia](/cell-types/microglia) clear [Aβ](/proteins/amyloid-beta-protein) via CSF1R-dependent mechanisms
- Neuroinflammation: CSF1R signaling can be protective or detrimental depending on context
- Genetic risk: CSF1R variants may modify AD risk
Parkinson's Disease
- Microglial activation: CSF1R mediates chronic neuroinflammation in PD
- [Alpha-synuclein](/proteins/alpha-synuclein) clearance: Microglial phagocytosis of α-synuclein
- Therapeutic targeting: CSF1R inhibitors being explored
Amyotrophic Lateral Sclerosis (ALS)
- Microglial heterogeneity: CSF1R+ microglia in ALS show disease-specific activation
- Neuroinflammation: Targeting CSF1R may modulate detrimental inflammation
- Therapeutic potential: CSF1R modulators in development
Multiple Sclerosis
- Demyelination: CSF1R signaling affects oligodendrocyte precursor cells
- Remyelination: Modulating microglia via CSF1R
- Therapeutic trials: CSF1R inhibitors in MS
Key Mutations
| Mutation | Type | Location | Frequency |
|----------|------|----------|-----------|
| p.Ile794Thr | Missense | Kinase domain | Common |
| p.Ala781Val | Missense | Kinase domain | Common |
| p.His888Arg | Missense | Kinase domain | Rare |
| p.Leu865Val | Missense | Kinase domain | Rare |
| p.Gln840Pro | Missense | Kinase domain | Rare |
| c.2380G>A | Splice site | Exon 18 | Rare |
Most pathogenic variants cluster in the tyrosine kinase domain (exons 12-22), impairing enzymatic function[@adams2020].
Diagnosis
Genetic Testing
- Targeted panel: CSF1R sequencing for leukoencephalopathy workup
- Whole exome sequencing: Used when phenotype suggests hereditary leukoencephalopathy
- Interpretation: Pathogenic/likely pathogenic variants confirm diagnosis
Neuroimaging
- MRI brain: T2/FLAIR hyperintensities in periventricular and deep white matter
- Diffusion tensor imaging: Reduced fractional anisotropy
- MRS: Elevated choline, decreased N-acetylaspartate
Cerebrospinal Fluid
- Routine analysis: Typically normal
- [Neurofilament light](/biomarkers/neurofilament-light-chain-nfl) chain (NfL): Often elevated (marker of axonal damage)
Treatment and Management
Current Approaches
No FDA-approved disease-modifying therapy exists for ALSP. Management includes[@mateen2022]:
Symptomatic treatment:
- Physical/occupational therapy
- Cognitive rehabilitation
- Psychiatric management
- Anti-spasticity medications (baclofen, tizanidine)
Monitoring:
- Regular MRI to track disease progression
- Neuropsychological testing
- Functional assessments
Emerging Therapies
CSF1R Agonists
- recombinant CSF1 (m-CSF): May enhance microglial function
- IL-34: Alternative ligand; potential therapeutic
- Small molecule agonists: In development
CSF1R Antagonists/Inhibitors
Paradoxically, CSF1R antagonists are being investigated for neurodegenerative diseases to modulate harmful neuroinflammation[@olmosalonso2021]:
| Drug | Type | Stage | Indication |
|------|------|-------|------------|
| PLX3397 (Pexidartinib) | Kinase inhibitor | Preclinical/Phase 1 | ALS, AD |
| PLX5622 | Kinase inhibitor | Preclinical | AD, PD, MS |
| BLZ945 | Kinase inhibitor | Preclinical | ALS, AD |
| JNJ-40346527 | Kinase inhibitor | Phase 1 | AD |
Gene Therapy
- AAV-vector delivery: Express wild-type CSF1R
- CRISPR-based approaches: Correct pathogenic variants
Microglial Repopulation
- Bone marrow transplantation: Experimental approach to replace dysfunctional microglia
- CSF1R-independent pathways: Exploring alternative microglial engraftment
Key Publications
[Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids](https://doi.org/10.1038/ng.1027). Nature Genetics, 2012. PMID: 22197934(https://pubmed.ncbi.nlm.nih.gov/22197934/)
[CSF1R-related leukoencephalopathy: a major player in primary microgliopathies](https://doi.org/10.1212/WNL.0000000000006559). Neurology, 2019. PMID: 30651363(https://pubmed.ncbi.nlm.nih.gov/30651363/)
[Colony-stimulating factor 1 receptor-related disorder](https://doi.org/10.1212/NXG.0000000000200179). Neurology Genetics, 2023.
[Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia: clinical and neuropathological features](https://doi.org/10.1093/brain/aww116). Brain, 2016. PMID: 26740088(https://pubmed.ncbi.nlm.nih.gov/26740088/)
[CSF1R inhibitor therapy for microglia-mediated neurodegeneration](https://doi.org/10.1038/nn.3706). Nature Neuroscience, 2014. PMID: 25482915(https://pubmed.ncbi.nlm.nih.gov/25482915/)
[Microglia in Alzheimer's disease: adaptive or maladaptive?](https://doi.org/10.1016/j.neuron.2023.04.012). Neuron, 2023.
[CSF1R signaling in brain development and disease](https://doi.org/10.1016/j.tins.2021.08.004). Trends in Neurosciences, 2021.
[Targeting microglia in neurodegenerative disease](https://doi.org/10.1038/s41582-020-0372-y). Nature Reviews Neurology, 2020.
[CSF1R mutations in ALSP: understanding genotype-phenotype correlations](https://doi.org/10.1212/WNL.0000000000013256). Neurology, 2022.
[Microglial replacement therapy: a new approach for neurodegenerative disease](https://doi.org/10.1016/j.stem.2023.05.015). Cell Stem Cell, 2023.
External Links
- NCBI Gene: [https://www.ncbi.nlm.nih.gov/gene/1436](https://www.ncbi.nlm.nih.gov/gene/1436)
- Ensembl: [https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000182578](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000182578)
- OMIM: [https://omim.org/entry/164770](https://omim.org/entry/164770)
- UniProt: [https://www.uniprot.org/uniprot/P07333](https://www.uniprot.org/uniprot/P07333)
- Allen Human Brain Atlas: [CSF1R expression](https://human.brain-map.org/microarray/search/show?search_term=CSF1R)
See Also
- [alsp](/diseases/alsp)
- [hdls](/diseases/hdls)
- [neurons](/entities/neurons)](/entities)
- [csf1r-inhibitors-neurodegeneration](/therapeutics/csf1r-inhibitors-neurodegeneration)](/therapeutics)
- [Genes Index](/genes)
- [Proteins Index
Background
The study of Csf1R — Colony Stimulating Factor 1 Receptor has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
Brain Atlas Resources
- [Allen Human Brain Atlas - CSF1R Expression](https://human.brain-map.org/microarray/search/show?search_term=CSF1R)](/datasets/allen-human-brain-atlas)
- [Allen Cell Type Atlas - CSF1R](https://celltypes.brain-map.org/)
- [BrainSpan - CSF1R Developmental Expression](https://brainspan.org/)
- [Allen Mouse Brain Atlas - CSF1R](https://mouse.brain-map.org/)
References
[Stanley ER, Chitu V, CSF-1 receptor signaling in myeloid cells (2014)](https://pubmed.ncbi.nlm.nih.gov/24825877/)
[Lin W, Xu D, Austin CD, et al, Function of CSF1 and IL-34 in microglia (2018)](https://pubmed.ncbi.nlm.nih.gov/29666163/)
[Ginhoux F, Greter M, Leboeuf M, et al, Fate mapping analysis reveals that adult microglia derive from primitive macrophages (2010)](https://pubmed.ncbi.nlm.nih.gov/20966214/)
[Rademakers R, Baker M, Nicholson AM, et al, Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids (2012)](https://pubmed.ncbi.nlm.nih.gov/22197934/)
[Konno T, Kasanuki K, Ikeuchi T, et al, CSF1R-related leukoencephalopathy: clinical, radiologic, and pathologic features (2018)](https://pubmed.ncbi.nlm.nih.gov/29669928/)
[Wang Y, Cella M, Wang L, et al, TREM2 maintains microglial metabolic fitness in Alzheimer's disease (2017)](https://pubmed.ncbi.nlm.nih.gov/28841419/)
[Adams SJ, Kirk A, Auer RN, Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP): overview of clinical features and CSF1R (2020)](https://pubmed.ncbi.nlm.nih.gov/32719644/)
[Mateen FJ, Mojan V,抱Kumar S, et al, CSF1R-related leukoencephalopathy: long-term outcomes and treatment (2022)](https://pubmed.ncbi.nlm.nih.gov/35115372/)
[Olmos-Alonso A, O'Hara K, Pearce LA, et al, Pharmacological inhibition of CSF1R by PLX3397 reduces microglial activation and disease progression in ALS mouse models (2021)](https://pubmed.ncbi.nlm.nih.gov/34181967/)Pathway Diagram
The following diagram shows the key molecular relationships involving CSF1R — Colony Stimulating Factor 1 Receptor discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)