| Symbol: | CSF1R |
| Also known as: | c-FMS, CD115, M-CSFR |
| UniProt: | [P07333](https://www.uniprot.org/uniprot/P07333) |
| Gene: | [CSF1R](/genes/csf1r) |
| MW: | 107.6 kDa |
| Location: | Cell membrane |
| PDB: | [3LCD](https://www.rcsb.org/structure/3LCD), [4W7E](https://www.rcsb.org/structure/4W7E) |
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[1].
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[2][3].
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:
Transmembrane Domain (residues 513-534): Single-pass α-helix anchoring the receptor
Intracellular Domain (residues 535-972): Contains:
Ligand binding induces receptor dimerization, trans-autophosphorylation, and activation of downstream signaling cascades[5].
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[6].
Survival: Continuous CSF1R signaling is required for microglial survival. CSF1R inhibition or knockout leads to rapid microglial depletion[7].
Homeostasis: CSF1R maintains microglial identity and the homeostatic microglial gene expression signature (Tmem119, P2ry12, Siglech).
Upon CSF-1 or IL-34 binding, CSF1R activates multiple downstream pathways:
| Pathway | Function |
|---|---|
| PI3K/AKT | Survival, metabolic regulation |
| RAS/RAF/MEK/ERK | Proliferation, differentiation |
| JAK/STAT | Gene expression, activation |
| SRC Family Kinases | Cytoskeletal remodeling, phagocytosis |
CSF1R-regulated microglial functions include:
Heterozygous mutations in CSF1R cause ALSP, characterized by:
Clinical Features:
Pathology:
Pathogenic Mutations:
Mechanism: Mutations impair microglial function, leading to:
CSF1R involvement in AD is complex:
DAM Activation: Disease-associated microglia (DAM) show increased CSF1R signaling, promoting neuroinflammation and phagocytosis of Aβ[11].
TREM2 Interaction: TREM2 and CSF1R signaling cooperate to regulate microglial responses to amyloid pathology[12].
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[13].
CSF1R in PD involves:
Microglial Activation: α-synuclein aggregates activate microglia via CSF1R-dependent pathways[14].
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[15].
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[16].
| Compound | Status | Application |
|---|---|---|
| PLX3397 (Pexidartinib) | FDA approved | Tenosynovial giant cell tumor; AD trials |
| BLZ945 | Clinical trials | MS, AD |
| PLX5622 | Preclinical/Clinical | Neurodegeneration research |
| JNJ-40346527 | Phase II | AD |
CSF1R inhibitors can achieve >90% microglial depletion:
Benefits:
Risks:
For CSF1R-related disorder:
Hematopoietic Stem Cell Transplantation (HSCT): Restores microglial function by replacing CSF1R-deficient cells[18].
Supportive Care: Symptomatic management of cognitive and motor symptoms.
Experimental Approaches: Gene therapy and small molecule chaperones under investigation.
| Interactor | Type | Function |
|---|---|---|
| CSF-1 | Ligand | Primary activator |
| IL-34 | Ligand | Alternative activator |
| SRC | Kinase | Downstream signaling |
| PI3K | Kinase | Survival signaling |
| GRB2 | Adaptor | RAS pathway activation |
| STAT3 | TF | Gene expression |
| TREM2 | Receptor | Cooperative signaling |
| DAP12 | Adaptor | TREM2 signaling |
Elmore MR, Najafi AR, Koike MA, et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability. Nat Neurosci. 2014. ↩︎
Rademakers R, Baker M, Nicholson AM, et al. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet. 2012. ↩︎
Guo L, Elzinga K, Wong G, et al. CSF1R mutations and neurodegeneration. Ann Neurol. 2019. ↩︎
Felix J, De Munck S, Verstraete K, et al. Structure and assembly mechanism of the signaling complex CSF-1/CSF-1R. Nat Commun. 2015. ↩︎
Stanley ER, Chitu V. CSF-1 receptor signaling in myeloid cells. Cold Spring Harb Perspect Biol. 2014. ↩︎
Ginhoux F, Greter M, Leboeuf M, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010. ↩︎
Elmore MR, Lee RJ, West BL, Green KN. Characterizing newly repopulated microglia. J Neuroinflammation. 2015. ↩︎
Salter MW, Stevens B. Microglia emerge as central players in brain disease. Nat Med. 2017. ↩︎
Konno T, Kasanuki K, Miyazaki Y, et al. Clinical features of CSF1R-related adult-onset leukoencephalopathy. J Neurol. 2018. ↩︎
Oosterhof N, Chang I, Karimiani EG, et al. CSF1R mutations in hereditary diffuse leukoencephalopathy with spheroids. Acta Neuropathol. 2019. ↩︎
Keren-Shaul H, Spinrad A, Weiner A, et al. A unique microglia type associated with restricting development of Alzheimer's disease. Cell. 2017. ↩︎
Mazaheri F, Snaidero N, Kleinberger G, et al. TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury. EMBO Rep. 2017. ↩︎
Olmos-Alcalá A, Padilla-Del Rey M, Sáiz-Sánchez D, et al. CSF1 and microglial activation in Alzheimer's disease. J Neuroinflammation. 2021. ↩︎
Zhang W, Wang T, Pei Z, et al. Aggregated alpha-synuclein activates microglia. J Neuroinflammation. 2005. ↩︎
Van Dyken P, Lockhart BP, Lakkaraju A, et al. CSF1R inhibition protects dopaminergic neurons. Neuropharmacology. 2020. ↩︎
Niu J, Tsai HH, Hoi KK, et al. Modulation of CSF1R signaling during demyelination. Nat Neurosci. 2022. ↩︎
Dagher NN, Najafi AR, Kayala KM, et al. Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association. Nat Commun. 2015. ↩︎
Mochizuki H, Hosomi N, Fukada S, et al. Hematopoietic stem cell transplantation for CSF1R-related disorder. Neurology. 2023. ↩︎