CSF1R Protein (Colony Stimulating Factor 1 Receptor)

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CSF1R Protein (Colony Stimulating Factor 1 Receptor)

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CSF1R Protein (Colony Stimulating Factor 1 Receptor)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">CSF1R Protein (Colony Stimulating Factor 1 Receptor)</th>
</tr>
<tr>
<td class="label">Pathway</td>
<td>Function</td>
</tr>
<tr>
<td class="label">PI3K/AKT</td>
<td>Survival, metabolic regulation</td>
</tr>
<tr>
<td class="label">RAS/RAF/MEK/ERK</td>
<td>Proliferation, differentiation</td>
</tr>
<tr>
<td class="label">JAK/STAT</td>
<td>Gene expression, activation</td>
</tr>
<tr>
<td class="label">SRC Family Kinases</td>
<td>Cytoskeletal remodeling, phagocytosis</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Status</td>
</tr>
<tr>
<td class="label">PLX3397 (Pexidartinib)</td>
<td>FDA approved</td>
</tr>
<tr>
<td class="label">BLZ945</td>
<td>Clinical trials</td>
</tr>
<tr>
<td class="label">PLX5622</td>
<td>Preclinical/Clinical</td>
</tr>
<tr>
<td class="label">JNJ-40346527</td>
<td>Phase II</td>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Type</td>
</tr>
<tr>
<td class="label">CSF-1</td>
<td>Ligand</td>
</tr>
<tr>
<td class="label">IL-34</td>
<td>Ligand</td>
</tr>
<tr>
<td class="label">SRC</td>
<td>Kinase</td>
</tr>
<tr>
<td class="label">PI3K</td>
<td>Kinase</td>
</tr>
<tr>
<td class="label">GRB2</td>
<td>Adaptor</td>
</tr>
<tr>
<td class="label">STAT3</td>
<td>TF<

...

CSF1R Protein (Colony Stimulating Factor 1 Receptor)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">CSF1R Protein (Colony Stimulating Factor 1 Receptor)</th>
</tr>
<tr>
<td class="label">Pathway</td>
<td>Function</td>
</tr>
<tr>
<td class="label">PI3K/AKT</td>
<td>Survival, metabolic regulation</td>
</tr>
<tr>
<td class="label">RAS/RAF/MEK/ERK</td>
<td>Proliferation, differentiation</td>
</tr>
<tr>
<td class="label">JAK/STAT</td>
<td>Gene expression, activation</td>
</tr>
<tr>
<td class="label">SRC Family Kinases</td>
<td>Cytoskeletal remodeling, phagocytosis</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Status</td>
</tr>
<tr>
<td class="label">PLX3397 (Pexidartinib)</td>
<td>FDA approved</td>
</tr>
<tr>
<td class="label">BLZ945</td>
<td>Clinical trials</td>
</tr>
<tr>
<td class="label">PLX5622</td>
<td>Preclinical/Clinical</td>
</tr>
<tr>
<td class="label">JNJ-40346527</td>
<td>Phase II</td>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Type</td>
</tr>
<tr>
<td class="label">CSF-1</td>
<td>Ligand</td>
</tr>
<tr>
<td class="label">IL-34</td>
<td>Ligand</td>
</tr>
<tr>
<td class="label">SRC</td>
<td>Kinase</td>
</tr>
<tr>
<td class="label">PI3K</td>
<td>Kinase</td>
</tr>
<tr>
<td class="label">GRB2</td>
<td>Adaptor</td>
</tr>
<tr>
<td class="label">STAT3</td>
<td>TF</td>
</tr>
<tr>
<td class="label">TREM2</td>
<td>Receptor</td>
</tr>
<tr>
<td class="label">DAP12</td>
<td>Adaptor</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>

<div style="float: right; width: 280px; background: #f8f9fa; padding: 12px; border: 1px solid #ddd; border-radius: 4px; margin: 0 0 1em 1em; font-size: 0.9em;">
<h3 style="margin-top: 0; border-bottom: 1px solid #ccc;">CSF1R Protein</h3>
<table style="width: 100%; border-collapse: collapse;">
<tr><td style="padding: 4px 0;"><strong>Symbol:</strong></td><td>CSF1R</td></tr>
<tr><td style="padding: 4px 0;"><strong>Also known as:</strong></td><td>c-FMS, CD115, M-CSFR</td></tr>
<tr><td style="padding: 4px 0;"><strong>UniProt:</strong></td><td>[P07333](https://www.uniprot.org/uniprot/P07333)</td></tr>
<tr><td style="padding: 4px 0;"><strong>Gene:</strong></td><td>[CSF1R](/genes/csf1r)</td></tr>
<tr><td style="padding: 4px 0;"><strong>MW:</strong></td><td>107.6 kDa</td></tr>
<tr><td style="padding: 4px 0;"><strong>Location:</strong></td><td>Cell membrane</td></tr>
<tr><td style="padding: 4px 0;"><strong>PDB:</strong></td><td>[3LCD](https://www.rcsb.org/structure/3LCD), [4W7E](https://www.rcsb.org/structure/4W7E)</td></tr>
</table>
</div>

Pathway Diagram

Mermaid diagram (expand to render)

Overview

CSF1R (Colony Stimulating Factor 1 Receptor, also known as c-FMS, CD115, or M-CSFR) is a receptor tyrosine kinase that plays essential roles in microglial development, survival, and function. As the primary receptor for colony stimulating factor 1 (CSF-1, also called M-CSF) and interleukin-34 (IL-34), CSF1R signaling is critical for the maintenance and activation of the brain's resident immune cells[@elmore2014].

CSF1R mutations cause adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare but devastating neurodegenerative disorder. Additionally, CSF1R signaling is implicated in Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions through its effects on microglial function[@rademakers2012][@guo2019].

Structure and Domain Architecture

CSF1R is a 972-amino acid transmembrane protein belonging to the platelet-derived growth factor receptor (PDGFR) family:

Extracellular Domain (residues 1-512): Contains five immunoglobulin-like (Ig-like) domains responsible for ligand binding:

D1-D3: Primary ligand binding sites for CSF-1 and IL-34
D4-D5: Receptor dimerization interface[@felix2015]

Transmembrane Domain (residues 513-534): Single-pass α-helix anchoring the receptor

Intracellular Domain (residues 535-972): Contains:

Juxtamembrane Domain: Autoinhibitory region
Tyrosine Kinase Domain (residues 578-910): Split kinase domain with intervening sequence
C-terminal Tail: Contains additional tyrosine phosphorylation sites

Ligand binding induces receptor dimerization, trans-autophosphorylation, and activation of downstream signaling cascades[@stanley2014].

Normal Function in the CNS

Microglial Development and Survival

CSF1R is the master regulator of microglial biology:

Development: CSF1R signaling is essential for microglial precursor migration from the yolk sac to the developing brain and subsequent proliferation[@ginhoux2010].
Survival: Continuous CSF1R signaling is required for microglial survival. CSF1R inhibition or knockout leads to rapid microglial depletion[@elmore2015].
Homeostasis: CSF1R maintains microglial identity and the homeostatic microglial gene expression signature (Tmem119, P2ry12, Siglech).

Signaling Pathways

Upon CSF-1 or IL-34 binding, CSF1R activates multiple downstream pathways:

Microglial Functions

CSF1R-regulated microglial functions include:

Synaptic Pruning: [Microglia](/cell-types/microglia-neuroinflammation) eliminate excess synapses during development

Debris Clearance: Phagocytosis of apoptotic cells and protein aggregates

Neurotrophic Support: Secretion of growth factors (IGF-1, BDNF)

Immune Surveillance: Monitoring for pathogens and damage signals[@salter2017]

Role in Neurodegeneration

Heterozygous mutations in CSF1R cause ALSP, characterized by:

Clinical Features:

Onset typically 40-50 years
Cognitive decline, personality changes
Motor dysfunction, pyramidal signs
Seizures and leukoencephalopathy[@konno2018]

Pathology:

White matter degeneration with axonal spheroids
Pigmented glia containing lipofuscin
Microglial dysfunction and depletion

Pathogenic Mutations:

Over 50 mutations identified
Kinase domain mutations most common
Both loss-of-function and dominant-negative effects[@oosterhof2019]

Mechanism: Mutations impair microglial function, leading to:

Defective myelin clearance
Accumulation of axonal spheroids
Secondary oligodendrocyte and axonal damage

Alzheimer's Disease

CSF1R involvement in AD is complex:

DAM Activation: Disease-associated microglia (DAM) show increased CSF1R signaling, promoting neuroinflammation and phagocytosis of [Aβ](/proteins/amyloid-beta)[@kerenshaul2017].

[TREM2](/proteins/trem2) Interaction: TREM2 and CSF1R signaling cooperate to regulate microglial responses to amyloid pathology[@mazaheri2017].

Therapeutic Targeting: CSF1R inhibitors reduce microglial proliferation but may impair protective functions.

CSF1 Levels: Elevated CSF1 in AD brain correlates with disease severity and may contribute to microglial dysregulation[@olmosalcal2021].

Parkinson's Disease

CSF1R in PD involves:

Microglial Activation: [α-synuclein](/proteins/alpha-synuclein) aggregates activate microglia via CSF1R-dependent pathways[@zhang2005].

Neuroinflammation: CSF1R signaling promotes pro-inflammatory cytokine release from microglia.

Dopaminergic Neurodegeneration: Microglial activation via CSF1R contributes to dopaminergic neuron loss.

Neuroprotective Potential: Some studies suggest CSF1R inhibition may be protective by reducing neuroinflammation[@van2020].

Multiple Sclerosis

CSF1R contributes to MS pathophysiology:

Microglial Activation: Active MS lesions show increased CSF1R+ microglia.

Demyelination: CSF1R signaling promotes microglial phagocytosis of myelin.

Therapeutic Considerations: CSF1R inhibitors may reduce lesion activity but risk impairing repair[@niu2022].

Therapeutic Targeting

CSF1R Inhibitors

Microglial Depletion Strategy

CSF1R inhibitors can achieve >90% microglial depletion:

Benefits:

Reduces neuroinflammation
Allows study of microglial function
May remove dysfunctional microglia[@dagher2015]

Risks:

Impairs debris clearance
Disrupts synaptic homeostasis
May worsen pathology in some contexts

ALSP Treatment

For CSF1R-related disorder:

Hematopoietic Stem Cell Transplantation (HSCT): Restores microglial function by replacing CSF1R-deficient cells[@mochizuki2023].

Supportive Care: Symptomatic management of cognitive and motor symptoms.

Experimental Approaches: Gene therapy and small molecule chaperones under investigation.

Key Interactions

References

[Elmore MR, Najafi AR, Koike MA, et al, Colony-stimulating factor 1 receptor signaling is necessary for microglia viability (2014)](https://doi.org/10.1038/nn.3810)

[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://doi.org/10.1038/ng.1027)

[Guo L, Elzinga K, Wong G, et al, CSF1R mutations and neurodegeneration (2019)](https://doi.org/10.1002/ana.25387)

[Felix J, De Munck S, Verstraete K, et al, Structure and assembly mechanism of the signaling complex CSF-1/CSF-1R (2015)](https://doi.org/10.1038/ncomms7927)

[Stanley ER, Chitu V, CSF-1 receptor signaling in myeloid cells (2014)](https://doi.org/10.1101/cshperspect.a021859)

[Ginhoux F, Greter M, Leboeuf M, et al, Fate mapping analysis reveals that adult microglia derive from primitive macrophages (2010)](https://doi.org/10.1126/science.1194637)

[Elmore MR, Lee RJ, West BL, Green KN, Characterizing newly repopulated microglia (2015)](https://doi.org/10.1186/s12974-015-0399-7)

[Salter MW, Stevens B, Microglia emerge as central players in brain disease (2017)](https://doi.org/10.1038/nm.4397)

[Konno T, Kasanuki K, Miyazaki Y, et al, Clinical features of CSF1R-related adult-onset leukoencephalopathy (2018)](https://doi.org/10.1007/s00415-018-8961-7)

[Oosterhof N, Chang I, Karimiani EG, et al, CSF1R mutations in hereditary diffuse leukoencephalopathy with spheroids (2019)](https://doi.org/10.1007/s00401-018-1945-0)

[Keren-Shaul H, Spinrad A, Weiner A, et al, A unique microglia type associated with restricting development of Alzheimer's disease (2017)](https://doi.org/10.1016/j.cell.2017.05.018)

[Mazaheri F, Snaidero N, Kleinberger G, et al, TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury (2017)](https://doi.org/10.15252/embr.201743435)

[Olmos-Alcalá A, Padilla-Del Rey M, Sáiz-Sánchez D, et al, CSF1 and microglial activation in Alzheimer's disease (2021)](https://doi.org/10.1186/s12974-021-02257-8)

[Zhang W, Wang T, Pei Z, et al, Aggregated alpha-synuclein activates microglia (2005)](https://doi.org/10.1186/1742-2094-2-14)

[Van Dyken P, Lockhart BP, Lakkaraju A, et al, CSF1R inhibition protects dopaminergic neurons (2020)](https://doi.org/10.1016/j.neuropharm.2019.108104)

[Niu J, Tsai HH, Hoi KK, et al, Modulation of CSF1R signaling during demyelination (2022)](https://doi.org/10.1038/s41593-022-01163-2)

[Dagher NN, Najafi AR, Kayala KM, et al, Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association (2015)](https://doi.org/10.1038/ncomms8425)

[Mochizuki H, Hosomi N, Fukada S, et al, Hematopoietic stem cell transplantation for CSF1R-related disorder (2023)](https://doi.org/10.1212/WNL.0000000000207534)

Pathway Diagram

The following diagram shows the key molecular relationships involving CSF1R Protein (Colony Stimulating Factor 1 Receptor) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

CSF1R

▸Metadataorigin_type: v1_polymorphic_backfill

slug	proteins-csf1r
kg_node_id	CSF1R
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-fd96d6d742bd
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-csf1r'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

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Certainty

100%

Debates

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Incoming

47

Outgoing

105

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

CSF1R Protein (Colony Stimulating Factor 1 Receptor)

CSF1R Protein (Colony Stimulating Factor 1 Receptor)

CSF1R Protein (Colony Stimulating Factor 1 Receptor)

Pathway Diagram

Overview

Structure and Domain Architecture

Normal Function in the CNS

Microglial Development and Survival

Signaling Pathways

Microglial Functions

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Multiple Sclerosis

Therapeutic Targeting

CSF1R Inhibitors

Microglial Depletion Strategy

ALSP Treatment

Key Interactions

See Also

References

Pathway Diagram

💬 Discussion

📗 Cite This Artifact

CSF1R Protein (Colony Stimulating Factor 1 Receptor)

CSF1R Protein (Colony Stimulating Factor 1 Receptor)

CSF1R Protein (Colony Stimulating Factor 1 Receptor)

Pathway Diagram

Overview

Structure and Domain Architecture

Normal Function in the CNS

Microglial Development and Survival

Signaling Pathways

Microglial Functions

Role in Neurodegeneration

ALSP (CSF1R-Related Disorder)

Alzheimer's Disease

Parkinson's Disease

Multiple Sclerosis

Therapeutic Targeting

CSF1R Inhibitors

Microglial Depletion Strategy

ALSP Treatment

Key Interactions

See Also

References

Pathway Diagram

💬 Discussion