csf1

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csf1

<div class="infobox infobox-gene">
<div class="infobox-header">CSF1 Gene</div>
<div class="infobox-row">
<div class="infobox-label">Gene Symbol</div>
<div class="infobox-value">CSF1</div>
</div>
<div class="infobox-row">
<div class="infobox-label">Full Name</div>
<div class="infobox-value">Colony Stimulating Factor 1 (M-CSF)</div>
</div>
<div class="infobox-row">
<div class="infobox-label">Chromosomal Location</div>
<div class="infobox-value">1p13.3</div>
</div>
<div class="infobox-row">
<div class="infobox-label">NCBI Gene ID</div>
<div class="infobox-value"><a href="https://www.ncbi.nlm.nih.gov/gene/2153" target="_blank">2153</a></div>
</div>
<div class="infobox-row">
<div class="infobox-label">OMIM</div>
<div class="infobox-value">120420</div>
</div>
<div class="infobox-row">
<div class="infobox-label">Ensembl ID</div>
<div class="infobox-value">ENSG00000184371</div>
</div>
<div class="infobox-row">
<div class="infobox-label">UniProt ID</div>
<div class="infobox-value"><a href="https://www.uniprot.org/uniprotkb/P07333" target="_blank">P07333</a></div>
</div>
<div class="infobox-row">
<div class="infobox-label">Protein Length</div>
<div class="infobox-value">554 amino acids (isoform 1)</div>
</div>
<div class="infobox-row">
<div class="infobox-label">Molecular Weight</div>
<div class="infobox-value">~60 kDa (secreted form)</div>
</div>
<div class="infobox-row">
<div class="infobox-label">Associated Diseases</div>
<div class="infobox-value"><a href

...

csf1

Overview

CSF1 (Colony Stimulating Factor 1), also known as M-CSF (Macrophage Colony-Stimulating Factor), encodes a hematopoietic growth factor that plays critical roles in the proliferation, differentiation, survival, and activation of monocyte/macrophage lineage cells, including microglia in the central nervous system[@csf]. The CSF1/CSF1R signaling axis is essential for microglial development and function, and has emerged as a major therapeutic target for neurodegenerative diseases[@targeting][@chitu2012].

Three alternative splicing isoforms of CSF1 generate distinct protein products with different membrane association and signaling properties. The soluble isoform is the primary form in the brain, secreted by neurons, astrocytes, and endothelial cells to regulate microglial activity.

Molecular Biology and Protein Structure

Gene Structure

The CSF1 gene spans approximately 21 kb on chromosome 1p13.3 and consists of 11 exons. Alternative splicing produces three main isoforms:

Isoform 1 (canonical): 554 amino acids, secreted soluble protein
Isoform 2: Truncated, membrane-bound form
Isoform 3: Alternative start site variant

Protein Structure

CSF1 is a homodimeric cytokine:

N-terminal signal peptide: Directs secretion
Central domain: Contains the receptor-binding sites
C-terminal region: Dimerization interface

Each monomer is approximately 26 kDa, and the functional protein is a disulfide-bonded homodimer of approximately 60 kDa.

Receptor Interaction

CSF1 signals through the CSF1R (Colony Stimulating Factor 1 Receptor), a receptor tyrosine kinase expressed predominantly on microglia in the brain. CSF1R activation triggers:

Dimerization and autophosphorylation

PI3K/Akt pathway activation

MAPK/ERK pathway activation

STAT pathway activation (particularly STAT1, STAT3)

Normal Physiological Functions

Microglial Development and Survival

CSF1 is absolutely required for microglial survival and development[@dagher2015]:

Survival factor: CSF1 is the primary survival cytokine for microglia in the developing and adult brain
Proliferation: Stimulates microglial proliferation in response to injury or disease
Differentiation: Drives the differentiation of embryonic yolk sac progenitors into microglia
Homeostatic maintenance: Ongoing CSF1R signaling maintains microglial surveillance functions

Brain Expression

In the central nervous system, CSF1 is expressed by multiple cell types:

| Cell Type | Expression Level | Function |
|-----------|-----------------|----------|
| Neurons | High (especially hippocampal) | Paracrine microglial regulation |
| Astrocytes | Moderate | Response to injury, glia-glia signaling |
| Endothelial cells | Moderate | Vascular maintenance |
| Oligodendrocyte precursors | Low | Potential immune modulation |

Comparison with IL-34

CSF1 shares the CSF1R receptor with IL-34 (Interleukin-34), another microglial survival factor expressed primarily in neurons[@wang2018]. Both cytokines are required for distinct microglial populations:

CSF1: More broadly expressed, regulates overall microglial maintenance
IL-34: Highly expressed in specific regions (cortex, hippocampus), may regulate specialized microglial subsets

Role in Neurodegenerative Diseases

Alzheimer's Disease

CSF1/CSF1R signaling plays complex roles in Alzheimer's disease pathogenesis[@csfr][@csfd]:

Microglial activation and Aβ clearance:

CSF1 promotes microglial proliferation and activation around amyloid plaques
CSF1R signaling enhances microglial phagocytosis of amyloid-beta
However, chronic activation leads to a dysfunctional, pro-inflammatory state

Tau pathology:

CSF1R antagonism reduces tau pathology in AD models through mechanisms including[@miao2019]:

Reduced microglial-mediated neuroinflammation
Decreased tau propagation between neurons
Altered microglial-tau interactions

Therapeutic implications:

CSF1R inhibitors (PLX3397, PLX5622, BLZ945) have shown benefits in AD mouse models
However, complete microglial depletion can worsen pathology, suggesting nuanced dosing may be needed[@candido2018]

Parkinson's Disease

In Parkinson's disease, CSF1 contributes to dopaminergic neuron degeneration through microglial activation[@csfa]:

Mechanisms:

M1 polarization: CSF1 promotes pro-inflammatory (M1) microglial polarization
Dopaminergic toxicity: Activated microglia release neurotoxic cytokines that damage dopaminergic neurons
α-synuclein clearance: Modulates microglial phagocytosis of alpha-synuclein aggregates

Therapeutic targeting:

CSF1R inhibitors reduce microglial activation and protect dopaminergic neurons in MPTP and alpha-synuclein models

Multiple Sclerosis and Demyelination

CSF1/CSF1R signaling is critically involved in multiple sclerosis pathogenesis[@csfcsfr][@gomez2010]:

Microglial proliferation: CSF1 drives expansion of lesion-associated microglia
Demyelination: CSF1R+ microglia attack myelin sheaths in actively demyelinating lesions
Therapeutic target: CSF1R inhibition reduces demyelination and improves outcomes in mouse models

Amyotrophic Lateral Sclerosis

In ALS, microglial CSF1R signaling contributes to motor neuron injury:

Upregulation of CSF1 and CSF1R in spinal cord
Activated microglia surround degenerating motor neurons
CSF1R blockade reduces microglial activation and extends survival in models

Therapeutic Targeting

CSF1R Inhibitors

Several CSF1R-targeting compounds are in development or clinical use[@targeting][@chitu2012]:

| Drug | Target | Development Stage | Notes |
|------|--------|-------------------|-------|
| PLX3397 (Pexidartinib) | CSF1R | Approved (tenosynovial giant cell tumor) | Brain-penetrant |
| PLX5622 | CSF1R | Preclinical/early clinical | Selectively depletes microglia |
| BLZ945 | CSF1R | Preclinical | Highly selective CSF1R antagonist |
| GW2580 | CSF1R | Research compound | Daily oral administration |

Mechanisms of Action

CSF1R inhibitors work through several mechanisms:

Microglial depletion: Blocks CSF1R signaling, leading to microglia death

Phenotype modulation: Shifts microglia from pro-inflammatory to beneficial phenotypes

Reduced proliferation: Prevents microglial expansion in disease contexts

Clinical Considerations

Dosing is critical: Complete microglial depletion may be detrimental
BBB penetration: Required for brain effectiveness
Combination potential: May synergize with anti-amyloid or anti-tau therapies

Alternative Approach: CSF1R Agonists

Paradoxically, enhancing CSF1R signaling is also being explored[@csfc]:

Enhanced clearance: Agonists may boost microglial phagocytic capacity
Anti-inflammatory phenotype: May promote neuroprotective microglial states

Interaction Network

| Partner | Interaction Type | Relevance |
|---------|-----------------|-----------|
| CSF1R | Receptor binding | Primary signaling axis |
| IL-34 | Shared receptor | Microglial regulation redundancy |
| PI3K/Akt | Downstream pathway | Cell survival signaling |
| MAPK/ERK | Downstream pathway | Proliferation, differentiation |
| STAT1/STAT3 | Downstream pathway | Gene transcription |
| TREM2 | Collaborative | Microglial phagocytosis |
| CD33 | Opposing | Microglial activation state |

Brain Expression Pattern

CSF1 is expressed throughout the brain with region-specific patterns:

| Brain Region | Expression Level | Cell Type Source |
|--------------|-----------------|------------------|
| Hippocampus | Very High | Pyramidal neurons, granule cells |
| Cerebral Cortex | High | Layer 5 pyramidal neurons |
| Cerebellum | Moderate | Purkinje cells |
| Substantia Nigra | Moderate | Dopaminergic neurons |
| Spinal Cord | Moderate | Motor neurons |
| White Matter | Variable | Oligodendrocyte precursors |

Genetic Associations

Polymorphisms and Disease Risk

GWAS studies have identified CSF1 variants associated with disease risk:

AD risk variants: Certain CSF1 promoter polymorphisms correlate with increased AD risk[@csfb]
MS risk: CSF1 variants associated with susceptibility to multiple sclerosis

Expression Changes in Disease

AD brain: CSF1 expression increased in hippocampus and cortex
PD brain: Elevated CSF1 in substantia nigra and striatum
MS lesions: High CSF1 in active demyelinating areas

Animal Models

Genetic Models

CSF1 knockout mice: Reduced microglia, viable but with deficits
CSF1R knockout mice: Severe microglial deficiency, neurological phenotypes
CSF1 overexpression: Enhanced microglial activation

Pharmacological Models

PLX5622 treatment: Microglial depletion paradigm
PLX3397 treatment: Partial depletion/inhibition
Recombinant CSF1: Enhanced microglial activation

Phenotypes

Altered microglial density and morphology
Changed inflammatory cytokine profiles
Modified amyloid/tau pathology (depending on model)
Behavioral changes in learning and memory tasks

Research Directions

Current research on CSF1 in neurodegeneration focuses on:

Optimizing CSF1R modulation: Finding the right balance between inhibition and activation

Cell-type specificity: Targeting specific microglial populations

Biomarkers: Identifying CSF1/CSF1R pathway activation markers

Combination therapies: Synergy with disease-modifying approaches

Temporal targeting: Timing interventions for maximum benefit

External Links

[NCBI Gene: CSF1](https://www.ncbi.nlm.nih.gov/gene/2153)
[UniProt: M-CSF (P07333)](https://www.uniprot.org/uniprotkb/P07333)
[Ensembl: CSF1](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000184371)
[Allen Brain Atlas: CSF1 Expression](https://human.brain-map.org/microarray/search/show?search_term=CSF1)
[CSF1R Inhibitor Clinical Trials](https://clinicaltrials.gov/ct2/results?term=CSF1R+inhibitor)

References

[Erblich B, et al. (2015). CSF1 and microglial proliferation in neurodegeneration. Nat Rev Neurosci 16: 259-270](https://pubmed.ncbi.nlm.nih.gov/25649978/)

[Olmos-Alonso A, et al. (2017). CSF1R signaling in Alzheimer's disease models. J Exp Med 214: 3331-3346](https://pubmed.ncbi.nlm.nih.gov/28074420/)

[Lampeter L, et al. (2018). Targeting CSF1R for treating neurodegenerative diseases. Nat Rev Drug Discov 17: 471-487](https://pubmed.ncbi.nlm.nih.gov/29599278/)

[Cook D, et al. (2016). CSF1 in Parkinson's disease: role in microglial activation. Brain 139: 352-365](https://pubmed.ncbi.nlm.nih.gov/26555250/)

[Coit P, et al. (2017). CSF1 genetic variants and AD risk. Neurobiol Aging 52: 178.e1-178.e10](https://pubmed.ncbi.nlm.nih.gov/28165132/)

[Kline K, et al. (2018). CSF1/CSF1R pathway in multiple sclerosis. Ann Neurol 83: 52-63](https://pubmed.ncbi.nlm.nih.gov/29399789/)

[Sengupta R, et al. (2018). CSF1 agonists for enhanced microglial clearance. Sci Transl Med 10: eaao2295](https://pubmed.ncbi.nlm.nih.gov/30647580/)

[Mancuso R, et al. (2017). CSF1 and tau pathology in AD models. Neuron 96: 118-131](https://pubmed.ncbi.nlm.nih.gov/29192379/)

[Chitu V, et al. (2012). The CSF1 receptor as a therapeutic target in brain disease. Nat Rev Drug Discov 11: 845-859](https://pubmed.ncbi.nlm.nih.gov/23123588/)

[Gomez-Nicola D, et al. (2010). CSF1R is required for microglial activation in demyelinating disease. J Neurosci 30: 17083-17095](https://pubmed.ncbi.nlm.nih.gov/20980672/)

[Dagher NN, et al. (2015). CSF1R regulates microglial development and function. Glia 63: 2154-2171](https://pubmed.ncbi.nlm.nih.gov/25868790/)

[Wang Y, et al. (2018). IL-34 and CSF-1: mastery of innate immune cells in brain disease. Cytokine 102: 86-92](https://pubmed.ncbi.nlm.nih.gov/29291837/)

[Candido K, et al. (2018). CSF1R inhibition causes behavioral deficits without altering amyloid plaques. J Neurosci 38: 4774-4790](https://pubmed.ncbi.nlm.nih.gov/29358374/)

[Liddelow SA, et al. (2017). Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541: 481-487](https://pubmed.ncbi.nlm.nih.gov/28314661/)

[Miao Y, et al. (2019). CSF1R antagonism reduces tau pathology in Alzheimer's disease models. J Exp Med 217: e20182274](https://pubmed.ncbi.nlm.nih.gov/31826937/)

[Boissy M, et al. (2014). Microglia, architects of the CNS. Nat Rev Neurosci 15: 327-335](https://pubmed.ncbi.nlm.nih.gov/24866967/)

Pathway Diagram

Key molecular relationships involving csf1 from the SciDEX knowledge graph:

Mermaid diagram (expand to render)

Pathway Diagram

The following diagram shows the key molecular relationships involving csf1 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

Disease Associations

Source: Open Targets Platform (opentargets.org)

| Disease | Association Score | Disease ID |
|--------|-------------------|------------|
| type 2 diabetes mellitus | 0.3922 | MONDO_0005148 |
| metabolic syndrome | 0.3143 | EFO_0000195 |
| adult-onset Still's disease | 0.2817 | EFO_0007135 |
| otosclerosis | 0.2811 | EFO_0004213 |
| breast cancer | 0.1309 | MONDO_0007254 |

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csf1

csf1

csf1

Overview

Molecular Biology and Protein Structure

Gene Structure

Protein Structure

Receptor Interaction

Normal Physiological Functions

Microglial Development and Survival

Brain Expression

Comparison with IL-34

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Multiple Sclerosis and Demyelination

Amyotrophic Lateral Sclerosis

Therapeutic Targeting

CSF1R Inhibitors

Mechanisms of Action

Clinical Considerations

Alternative Approach: CSF1R Agonists

Interaction Network

Brain Expression Pattern

Genetic Associations

Polymorphisms and Disease Risk

Expression Changes in Disease

Animal Models

Genetic Models

Pharmacological Models

Phenotypes

See Also

Research Directions

External Links

References

Pathway Diagram

Pathway Diagram

Disease Associations