CSF1R — Colony Stimulating Factor 1 Receptor

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CSF1R — Colony Stimulating Factor 1 Receptor

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CSF1R — Colony Stimulating Factor 1 Receptor

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">CSF1R — Colony Stimulating Factor 1 Receptor</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>CSF1R</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Colony Stimulating Factor 1 Receptor</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>5q32</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/1436" target="_blank">1436</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000182578" target="_blank">ENSG00000182578</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/164770" target="_blank">164770</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P07333" target="_blank">P07333</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>ALSP, HDLS</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>[Microglia](/cell-types/microglia), Macrophages, Osteoclasts, Placenta</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Mutations</th>
</tr>
<tr>
<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>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">AL

...

CSF1R — Colony Stimulating Factor 1 Receptor

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">CSF1R — Colony Stimulating Factor 1 Receptor</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>CSF1R</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Colony Stimulating Factor 1 Receptor</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>5q32</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/1436" target="_blank">1436</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000182578" target="_blank">ENSG00000182578</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/164770" target="_blank">164770</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P07333" target="_blank">P07333</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>ALSP, HDLS</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>[Microglia](/cell-types/microglia), Macrophages, Osteoclasts, Placenta</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Mutations</th>
</tr>
<tr>
<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>
</tr>
<tr>
<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>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">164 edges</a></td>
</tr>
</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 activated

Downstream 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)

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)

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Related Entities

CSF1R

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origin_type	v1_polymorphic_backfill
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📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

86

Outgoing

107

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

CSF1R — Colony Stimulating Factor 1 Receptor

CSF1R — Colony Stimulating Factor 1 Receptor

CSF1R — Colony Stimulating Factor 1 Receptor

CSF1R — Colony Stimulating Factor 1 Receptor

Pathway Diagram

Introduction

Overview

Function

CSF1R Signaling Pathway

Downstream Signaling Pathways

Role in Microglia

Brain Expression

Disease Associations

Adult-Onset Leukoencephalopathy with Spheroids and Pigmented Glia (ALSP)

Clinical Features

Pathophysiology

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

Multiple Sclerosis

Key Mutations

Diagnosis

Genetic Testing

Neuroimaging

Cerebrospinal Fluid

Treatment and Management

Current Approaches

Emerging Therapies

CSF1R Agonists

CSF1R Antagonists/Inhibitors

Gene Therapy

Microglial Repopulation

Key Publications

External Links

See Also

Background

Brain Atlas Resources

References

Pathway Diagram

💬 Discussion