Full Name
Colony Stimulating Factor 1 (M-CSF)
Chromosomal Location
1p13.3
Ensembl ID
ENSG00000184371
Protein Length
554 amino acids (isoform 1)
Molecular Weight
~60 kDa (secreted form)
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
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
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.
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)
¶ 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
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 |
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
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]
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
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
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 |
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
- 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
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
| 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 |
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 |
¶ 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
- 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
- CSF1 knockout mice: Reduced microglia, viable but with deficits
- CSF1R knockout mice: Severe microglial deficiency, neurological phenotypes
- CSF1 overexpression: Enhanced microglial activation
- PLX5622 treatment: Microglial depletion paradigm
- PLX3397 treatment: Partial depletion/inhibition
- Recombinant CSF1: Enhanced microglial activation
- Altered microglial density and morphology
- Changed inflammatory cytokine profiles
- Modified amyloid/tau pathology (depending on model)
- Behavioral changes in learning and memory tasks
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
- Erblich B, et al. (2015). CSF1 and microglial proliferation in neurodegeneration. Nat Rev Neurosci 16: 259-270
- Olmos-Alonso A, et al. (2017). CSF1R signaling in Alzheimer's disease models. J Exp Med 214: 3331-3346
- Lampeter L, et al. (2018). Targeting CSF1R for treating neurodegenerative diseases. Nat Rev Drug Discov 17: 471-487
- Cook D, et al. (2016). CSF1 in Parkinson's disease: role in microglial activation. Brain 139: 352-365
- Coit P, et al. (2017). CSF1 genetic variants and AD risk. Neurobiol Aging 52: 178.e1-178.e10
- Kline K, et al. (2018). CSF1/CSF1R pathway in multiple sclerosis. Ann Neurol 83: 52-63
- Sengupta R, et al. (2018). CSF1 agonists for enhanced microglial clearance. Sci Transl Med 10: eaao2295
- Mancuso R, et al. (2017). CSF1 and tau pathology in AD models. Neuron 96: 118-131
- Chitu V, et al. (2012). The CSF1 receptor as a therapeutic target in brain disease. Nat Rev Drug Discov 11: 845-859
- Gomez-Nicola D, et al. (2010). CSF1R is required for microglial activation in demyelinating disease. J Neurosci 30: 17083-17095
- Dagher NN, et al. (2015). CSF1R regulates microglial development and function. Glia 63: 2154-2171
- Wang Y, et al. (2018). IL-34 and CSF-1: mastery of innate immune cells in brain disease. Cytokine 102: 86-92
- Candido K, et al. (2018). CSF1R inhibition causes behavioral deficits without altering amyloid plaques. J Neurosci 38: 4774-4790
- Liddelow SA, et al. (2017). Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541: 481-487
- Miao Y, et al. (2019). CSF1R antagonism reduces tau pathology in Alzheimer's disease models. J Exp Med 217: e20182274
- Boissy M, et al. (2014). Microglia, architects of the CNS. Nat Rev Neurosci 15: 327-335