{"gene":"CSF1","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":1999,"finding":"CSF-1 activation of CSF-1R causes Cbl tyrosine phosphorylation, Cbl-CSF-1R association, and their simultaneous multiubiquitination at the plasma membrane, leading to rapid CSF-1R internalization and degradation. Cbl-/- macrophages fail to exhibit CSF-1R multiubiquitination and show slower CSF-1R internalization, demonstrating that Cbl positively regulates coordinated CSF-1R multiubiquitination and endocytosis to attenuate proliferative signaling.","method":"Gene-targeted knockout macrophages (Cbl-/-), Co-immunoprecipitation, ubiquitination assay, receptor internalization assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic KO with defined mechanistic readout, multiple orthogonal methods in one study","pmids":["10393178"],"is_preprint":false},{"year":2010,"finding":"CSF-1R phospho-Tyr-559 is required for binding of Src family kinases (SFKs), and this site is both necessary and sufficient for CSF-1-induced CSF-1R ubiquitination and tyrosine phosphorylation. c-Cbl-mediated CSF-1R ubiquitination (dependent on its E3 ligase activity) is required for a conformational change in the kinase domain enabling amplification of receptor tyrosine phosphorylation and full receptor activation.","method":"Site-directed mutagenesis of CSF-1R, c-Cbl-deficient macrophages, reconstitution with wild-type vs. ubiquitin ligase-dead C381A c-Cbl, SFK inhibitors","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with mutagenesis, genetic KO, and pharmacological inhibition as orthogonal methods","pmids":["21041311"],"is_preprint":false},{"year":2001,"finding":"M-CSF induces phosphorylation of transcription factors Mitf and TFE3 via a conserved MAPK consensus site, triggering recruitment of the coactivator p300. An unphosphorylatable mutant at this MAPK serine specifically fails to support formation of multinucleated osteoclasts, linking M-CSF/MAPK signaling to Mitf/TFE3 phosphorylation as a nuclear target required for osteoclast maturation.","method":"Phosphorylation assay, co-immunoprecipitation with p300, site-directed mutagenesis, cell differentiation assay in Mitf(mi/mi) osteoclasts","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis, co-IP, and functional differentiation assay with genetic mutant model, multiple orthogonal methods","pmids":["11684011"],"is_preprint":false},{"year":2013,"finding":"M-CSF directly induces expression of the myeloid master regulator PU.1 in single hematopoietic stem cells (HSCs) and instructs myeloid cell-fate change independently of selective survival or proliferation. In vivo, high systemic M-CSF drives M-CSF-receptor-dependent activation of endogenous PU.1 protein in single HSCs, causing a PU.1-dependent myeloid differentiation preference.","method":"Single-cell video imaging, single-cell gene expression analysis, PU.1 promoter reporter assay, in vivo M-CSF administration in mice, M-CSF receptor-deficient controls","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (single-cell imaging, reporter assay, in vivo genetic model), independently validated in vitro and in vivo","pmids":["23575636"],"is_preprint":false},{"year":2003,"finding":"M-CSF, TNF-alpha, and RANKL promote osteoclast survival through convergent signaling on mTOR/S6 kinase. M-CSF signals to Akt, and inhibition of PI3K, Akt, ERKs, geranylgeranylated proteins, or mTOR/S6K induces osteoclast apoptosis. mTOR regulates protein translation via S6K, 4E-BP1, and S6, and inhibition of translation by other mechanisms also induces osteoclast apoptosis.","method":"Pharmacological inhibition (rapamycin, PI3K inhibitors, ERK inhibitors), S6K phosphorylation assay, apoptosis assay, in vitro bone resorption assay","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with multiple inhibitors, single lab, functional apoptosis and resorption readouts","pmids":["14502240"],"is_preprint":false},{"year":2005,"finding":"TNF-alpha stimulates M-CSF gene expression in stromal cells via TNF-responsive stromal cells, and M-CSF in turn induces RANK expression in osteoclast precursors. Antibody blockade of the M-CSF receptor c-Fms selectively and completely arrested pathological osteoclastogenesis and bone resorption in inflammatory arthritis and TNF-injected mice.","method":"Chimeric bone marrow transplant mice (TNF receptor-deficient stromal vs. precursor cells), anti-c-Fms blocking antibody in vivo, TRACP 5b bone resorption marker measurement","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic chimera approach, receptor blockade, multiple in vivo readouts establishing pathway position of M-CSF between TNF-alpha and RANK induction","pmids":["16294221"],"is_preprint":false},{"year":2000,"finding":"M-CSF neutralization in vivo completely prevents the rise in osteoclast number, increase in bone resorption, and bone loss induced by ovariectomy. Estrogen deficiency induces M-CSF production through an Egr-1-dependent mechanism; Egr-1-deficient mice with maximally stimulated stromal M-CSF production show increased bone resorption reversed by anti-M-CSF antibody.","method":"In vivo M-CSF neutralizing antibody, ovariectomy model, Egr-1 knockout mice, bone resorption and mass measurements","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO combined with neutralizing antibody, multiple in vivo bone phenotype readouts, epistatic placement of Egr-1 upstream of M-CSF","pmids":["10792003"],"is_preprint":false},{"year":2009,"finding":"M-CSF preferentially activates PLCgamma2 and thereby ERK to stabilize c-Fos and stimulate C/EBPalpha(S21) phosphorylation in myeloid progenitors, favoring monocyte lineage commitment. ERK inhibition prevented M-CSF-induced c-Fos induction, reduced C/EBPalpha phosphorylation, and decreased colony-forming unit-monocytes, establishing a mechanistic pathway from M-CSF receptor to monocyte specification.","method":"Receptor-expressing Ba/F3 cells, lineage-negative murine marrow cells, ERK inhibitors, PLC inhibitors, colony assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection with multiple pathway inhibitors, functional colony assay, single lab","pmids":["19587381"],"is_preprint":false},{"year":1997,"finding":"CSF-1R autophosphorylation site Y807 is essential for the differentiation signal: its mutation completely abrogates differentiation and conversely increases M-CSF-dependent proliferation, suggesting Y807 controls a switch between growth and differentiation. Sites Y697, Y706, and Y721 in the kinase insert region augment but are not required for differentiation.","method":"Site-directed mutagenesis of CSF-1R tyrosine sites, expression in FDC-P1 myeloid cells, differentiation and proliferation assays","journal":"Molecular reproduction and development","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis with functional differentiation/proliferation readout, single lab","pmids":["8981370"],"is_preprint":false},{"year":2015,"finding":"M-CSF-induced macropinocytosis in macrophages proceeds through a sequential PI3K → PLC → DAG → PKC/Ras pathway. PIP3 (PI3K product) appears in cups prior to DAG; PLC inhibitor blocks M-CSF-induced but not PMA-induced macropinocytosis; Ras and PKC inhibitors block both. Akt inhibition does not block macropinocytosis despite Akt activation by M-CSF.","method":"Live-cell fluorescent lipid probes, pharmacological inhibitors (PI3K, PLC, PKC, Ras, Akt), macropinocytosis quantification","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal pharmacological inhibitors, live imaging, single lab","pmids":["25688212"],"is_preprint":false},{"year":2010,"finding":"IL-34 and M-CSF share the Fms receptor but differ in receptor binding domains, signal activation kinetics, and downstream biological activities. IL-34 induces stronger but more transient tyrosine phosphorylation of Fms and downstream molecules and more rapidly downregulates Fms. An anti-Fms MAb blocked both IL-34-Fms and M-CSF-Fms binding, but another MAb blocked only M-CSF-Fms binding, indicating distinct binding sites on Fms.","method":"Receptor binding competition assay with blocking MAbs, phosphorylation kinetics assay, cell growth/survival assay, migration assay, morphological analysis","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor binding competition with distinct MAbs, phosphorylation kinetics, multiple functional readouts, single lab","pmids":["20489731"],"is_preprint":false},{"year":2006,"finding":"M-CSF induces stable association of the M-CSF receptor cFms with alphaVbeta3 integrin in osteoclasts. The cFms-alphaVbeta3 complex also contains Pyk2, p130Cas, and c-Cbl. Association is induced by M-CSF but peaks after the peak of cFms tyrosine phosphorylation. Co-localization of both receptors occurs in the podosomal actin ring during adhesion on glass but not in the sealing zone on bone.","method":"Anion-exchange chromatography, sequential immunoprecipitation, co-localization by microscopy in osteoclasts","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — sequential purification and Co-IP, co-localization imaging, single lab","pmids":["16600665"],"is_preprint":false},{"year":2004,"finding":"HIV-1 Nef interferes with the M-CSF/M-CSF receptor signaling pathway through Hck activation. Nef-activated Hck constitutively associates with the M-CSF receptor complex, causing markedly diminished tyrosine phosphorylation/activation of the M-CSF receptor in response to M-CSF and consequent inhibition of M-CSF-mediated proliferation and macrophage differentiation.","method":"Conditionally active Nef construct in TF-1-fms myeloid cells, receptor tyrosine phosphorylation assay, co-immunoprecipitation, proliferation and differentiation assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of Nef-Hck-receptor complex, phosphorylation assay, functional proliferation/differentiation readout, single lab","pmids":["15626739"],"is_preprint":false},{"year":2001,"finding":"CSF-1 is expressed as a secreted glycoprotein, proteoglycan (circulating or matrix-bound), or biologically active cell-surface glycoprotein. A 3.13-kb CSF-1 promoter/first intron driving the membrane-spanning CSF-1 precursor transgene rescues all gross phenotypic defects of Csf1-null op/op mice, identifying new cellular sites of CSF-1 expression including ovarian granulosa cells, mammary ductal epithelium, testicular Leydig cells, serous acinar cells, and Paneth cells.","method":"Transgenic rescue of Csf1(op)/Csf1(op) null mice, lacZ reporter under same promoter, tissue CSF-1 protein measurements, hematopoietic parameter analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic rescue with comprehensive phenotypic and molecular characterization, multiple tissues examined","pmids":["11418465"],"is_preprint":false},{"year":2003,"finding":"M-CSF induces VEGF production and release from human monocytes in a dose-dependent manner. VEGF released by M-CSF-stimulated monocytes is biologically active as it induces tube formation in HUVECs, an effect blocked by anti-VEGF antibody.","method":"Human monocyte culture with recombinant M-CSF, VEGF ELISA, HUVEC tube formation assay, antibody neutralization","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional VEGF activity assay with antibody neutralization, dose-response, single lab","pmids":["12928417"],"is_preprint":false},{"year":2023,"finding":"Bone marrow Adipoq-lineage progenitors (but not mature adipocytes) are a major cellular source of M-CSF in bone marrow, expressing CSF1 at much higher levels than osteoblast lineage cells. Cell-specific deletion of Csf1 in Adipoq-lineage progenitors drastically reduces bone marrow macrophage and osteoclast generation, causing severe osteopetrosis, and significantly alleviates ovariectomy-induced osteoporosis.","method":"Cell-specific conditional knockout (Adipoq-Cre), bone histology, TRAP staining, flow cytometry, bone mass measurement, ovariectomy model","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple phenotypic readouts, comparison across multiple cell-type-specific deletions, replicated in two independent studies (PMID 36779851 and 36779854)","pmids":["36779851","36779854"],"is_preprint":false},{"year":2017,"finding":"Lymphatic endothelial cells (LECs) produce high levels of M-CSF (but not RANKL, IL-6, or TNF), and LEC-mediated osteoclast formation and bone resorption are blocked by an M-CSF neutralizing antibody or M-CSF receptor inhibitor Ki20227. Intra-tibial LEC injection in mice causes massive osteolysis with elevated serum and bone marrow M-CSF, reversed by Ki20227 treatment.","method":"LEC-osteoclast co-culture, M-CSF neutralizing antibody, Ki20227 pharmacological inhibition, intra-tibial LEC injection mouse model, micro-CT, ELISA","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody neutralization and pharmacological blockade with in vitro and in vivo readouts, single lab","pmids":["28052488"],"is_preprint":false},{"year":2012,"finding":"CSF-1R (expressed primarily on Paneth cells) directly supports Paneth cell maturation and thereby fashions the intestinal stem cell niche. GI-specific Csf1r deletion in young adult mice leads to Paneth cell loss, changed distribution of proliferating cells, and loss of Lgr5 and other stem cell marker expression. Csf1r-/- crypts in organoid culture show the Paneth cell defect is epithelial cell-intrinsic and affects stem cell activity.","method":"Conditional Csf1r knockout (GI-specific), intestinal organoid culture, immunohistochemistry for stem cell markers, 3D localization of CSF-1R","journal":"Stem cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with organoid culture validation, multiple stem cell marker readouts, single lab","pmids":["23314290"],"is_preprint":false},{"year":1996,"finding":"CSF-1 promotes neuronal survival and process outgrowth in vitro in a dose-dependent manner. Both CSF-1 and its receptor are expressed in developing mouse brain. CSF-1-null op/op mice exhibit abnormal brainstem auditory and visual evoked potentials and aberrant cortical neuronal function; daily CSF-1 injection of postnatal op/op mice largely rescues these neurological abnormalities.","method":"Neuronal culture with CSF-1 treatment, nuclease protection assay for CSF-1/receptor expression, electrophysiological assays (evoked potentials, intracortical recordings), in vivo CSF-1 rescue injections in op/op mice","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional assay plus in vivo rescue experiment, multiple electrophysiological readouts, single lab","pmids":["8787741"],"is_preprint":false},{"year":2019,"finding":"Mesothelial cells produce both membrane-bound and secreted CSF1 that sustain peritoneal macrophage proliferation and growth. Peritoneal macrophages are found in close proximity to mesothelial cells in the peritoneal cavity.","method":"CSF1 protein detection in mesothelial cells (membrane and secreted forms), peritoneal macrophage localization, co-culture/proximity analysis","journal":"European journal of immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic detail in abstract regarding methods used to establish functional dependence","pmids":["31251389"],"is_preprint":false},{"year":2005,"finding":"CSF-1 down-regulates OPG gene expression in dental follicle cells in vivo, enabling osteoclastogenesis required for tooth eruption. CSF-1-deficient toothless (tl/tl) rats show higher OPG expression in dental follicle than normal littermates; siRNA knockdown of CSF-1 mRNA in dental follicle cells causes OPG upregulation.","method":"Comparison of OPG expression in CSF-1-deficient vs. normal rats, siRNA knockdown of CSF-1 in dental follicle cells, OPG gene expression analysis","journal":"Journal of dental research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic deficiency model plus siRNA knockdown, two orthogonal approaches establishing CSF-1 regulation of OPG","pmids":["16109994"],"is_preprint":false},{"year":2002,"finding":"M-CSF activates Fms tyrosine kinase, which sequentially activates PI3K or PLCgamma, leading to activation of the small GTPase Rac, which regulates actin cytoskeletal reorganization in microglia. Iba1 (a macrophage/microglia-specific calcium-binding protein) is involved in the Rac signaling pathway downstream of M-CSF/PLCgamma.","method":"Intracellular signaling analysis in microglia, pathway inhibition/activation studies (described as review with experimental basis)","journal":"Glia","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review-style abstract summarizing experimental findings but limited methodological detail; single lab","pmids":["12379904"],"is_preprint":false},{"year":1992,"finding":"Smooth muscle cells from arteriosclerotic lesions express the M-CSF receptor c-fms and exhibit high-affinity M-CSF binding, unlike normal medial smooth muscle cells. M-CSF stimulation of these intimal smooth muscle cells causes tyrosine phosphorylation and increased cell proliferation.","method":"c-fms expression analysis, M-CSF binding assay, anti-phosphotyrosine immunoblot, cell proliferation assay, immunocytochemistry","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding assay, phosphorylation assay, and proliferation assay in primary cells, single lab","pmids":["1531986"],"is_preprint":false}],"current_model":"CSF1 (M-CSF) is a homodimeric cytokine that signals exclusively through its receptor tyrosine kinase CSF-1R (c-Fms) by inducing receptor dimerization, transphosphorylation at multiple intracellular tyrosine residues (notably Y559, Y721, Y807), and sequential activation of SFK/c-Cbl-mediated receptor ubiquitination required for full kinase activation; downstream it engages PI3K/Akt/mTOR, PLCgamma/ERK, and Rac/actin pathways to drive survival, proliferation, chemotaxis, and differentiation of monocytes, macrophages, osteoclasts, microglia, and dendritic cells, while also directly instructing myeloid lineage commitment in hematopoietic stem cells by inducing PU.1, and is produced locally by mesenchymal/stromal cells (including bone marrow Adipoq-lineage progenitors, mesothelial cells, smooth muscle cells, and endothelial cells) to regulate tissue-resident macrophage populations in a paracrine fashion."},"narrative":{"mechanistic_narrative":"CSF1 (M-CSF) is a stromal-derived cytokine that drives the survival, proliferation, differentiation, and lineage commitment of myeloid cells by activating its receptor tyrosine kinase CSF-1R (c-Fms) [PMID:23575636, PMID:16294221]. Receptor activation is gated by an ubiquitin-dependent amplification loop: CSF-1R phospho-Tyr-559 recruits Src family kinases, and c-Cbl-mediated, E3-ligase-dependent receptor ubiquitination drives a kinase-domain conformational change required for full receptor tyrosine phosphorylation, while the same Cbl-coordinated multiubiquitination also triggers receptor internalization and degradation to attenuate signaling [PMID:10393178, PMID:21041311]. The activated receptor branches into PI3K/Akt/mTOR-S6K signaling that sustains cell survival and translation [PMID:14502240], a PLCgamma2/ERK arm that stabilizes c-Fos and phosphorylates C/EBPalpha to specify monocyte commitment [PMID:19587381], and a PI3K→PLC→DAG→PKC/Ras cascade and Rac-dependent actin remodeling that govern macropinocytosis and cytoskeletal reorganization [PMID:25688212]. A distinct CSF-1R autophosphorylation site, Y807, acts as a switch between proliferation and differentiation [PMID:8981370]. In the nucleus, M-CSF/MAPK signaling phosphorylates Mitf/TFE3 to recruit p300 and enable osteoclast maturation [PMID:11684011], and at the level of stem cells M-CSF directly induces the master regulator PU.1 to instruct myeloid fate in single hematopoietic stem cells [PMID:23575636]. CSF1 is produced as secreted, proteoglycan, and cell-surface forms by diverse stromal sources — bone marrow Adipoq-lineage progenitors, lymphatic and other endothelial cells, mesothelial cells, and intimal smooth muscle cells — to sustain tissue-resident macrophage and osteoclast populations in a paracrine manner [PMID:11418465, PMID:36779851, PMID:36779854, PMID:28052488], and it is a central effector in pathological bone resorption, linking TNF-alpha and estrogen-deficiency signals to osteoclastogenesis [PMID:16294221, PMID:10792003]. Beyond myeloid biology, CSF-1R supports Paneth cell maturation and the intestinal stem cell niche [PMID:23314290] and promotes neuronal survival and function during brain development [PMID:8787741].","teleology":[{"year":1992,"claim":"Established that CSF1 acts through c-Fms beyond classical myeloid targets, showing pathologically altered cells can acquire receptor responsiveness.","evidence":"c-fms expression, M-CSF binding, phosphotyrosine immunoblot and proliferation assays in arteriosclerotic intimal smooth muscle cells","pmids":["1531986"],"confidence":"Medium","gaps":["Did not define downstream signaling branches engaged in smooth muscle cells","Mechanism of ectopic c-fms induction unresolved"]},{"year":1996,"claim":"Extended CSF1 function into the nervous system, demonstrating a non-myeloid trophic role in vivo.","evidence":"Neuronal culture survival/outgrowth assays, expression analysis, evoked-potential electrophysiology, and CSF-1 rescue injection in op/op mice","pmids":["8787741"],"confidence":"Medium","gaps":["Direct vs. microglia-mediated neuronal effect not separated","Receptor-bearing cell type mediating rescue not defined"]},{"year":1997,"claim":"Mapped the growth-versus-differentiation decision to a specific receptor autophosphorylation site, defining a molecular switch.","evidence":"Site-directed mutagenesis of CSF-1R tyrosines in FDC-P1 cells with differentiation/proliferation readouts","pmids":["8981370"],"confidence":"Medium","gaps":["Effector bound at Y807 not identified","Single cell-line context"]},{"year":1999,"claim":"Identified Cbl as the coordinator of CSF-1R ubiquitination and endocytosis, defining the negative-feedback arm of signaling.","evidence":"Cbl-/- macrophages, reciprocal Co-IP, ubiquitination and receptor internalization assays","pmids":["10393178"],"confidence":"High","gaps":["Did not yet show ubiquitination is required for receptor activation (later refined)","Specific lysines ubiquitinated not mapped"]},{"year":2000,"claim":"Placed CSF1 epistatically downstream of estrogen-deficiency signaling in bone loss, establishing it as a required mediator of osteoclastogenesis.","evidence":"In vivo M-CSF neutralizing antibody and Egr-1 knockout mice in an ovariectomy model with bone resorption/mass readouts","pmids":["10792003"],"confidence":"High","gaps":["Stromal cell type producing M-CSF not defined","Direct Egr-1 binding to the Csf1 promoter not shown"]},{"year":2001,"claim":"Defined a nuclear endpoint of M-CSF/MAPK signaling required for osteoclast maturation.","evidence":"Phosphorylation assays, p300 Co-IP, mutagenesis of a MAPK serine, and differentiation assays in Mitf(mi/mi) osteoclasts","pmids":["11684011"],"confidence":"High","gaps":["Direct kinase phosphorylating Mitf/TFE3 not identified","Target genes driven by p300 recruitment not enumerated"]},{"year":2001,"claim":"Defined the molecular forms and tissue sources of CSF1 and proved the membrane-spanning precursor is sufficient to rescue the null phenotype.","evidence":"Transgenic rescue of Csf1(op)/op mice with a precursor transgene plus lacZ reporter and tissue protein measurements","pmids":["11418465"],"confidence":"High","gaps":["Relative functional contributions of secreted vs. membrane forms not dissected","Cell-autonomous requirement at each new site not tested"]},{"year":2002,"claim":"Outlined the Fms→PI3K/PLCgamma→Rac→actin axis governing microglial cytoskeletal responses.","evidence":"Signaling/pathway analysis in microglia (review-style with experimental basis)","pmids":["12379904"],"confidence":"Low","gaps":["Review-style abstract with limited methodological detail","Iba1 role in the pathway not mechanistically resolved"]},{"year":2003,"claim":"Mapped M-CSF survival signaling to convergent mTOR/S6K-dependent translation control in osteoclasts.","evidence":"Pharmacological inhibition of PI3K/Akt/ERK/mTOR with apoptosis and bone resorption assays","pmids":["14502240"],"confidence":"Medium","gaps":["Inhibitor-based dissection without genetic confirmation","Convergence point of M-CSF, TNF, RANKL not molecularly defined"]},{"year":2003,"claim":"Established that M-CSF instructs macrophages to secrete biologically active VEGF, linking the cytokine to angiogenesis.","evidence":"Human monocyte culture, VEGF ELISA, HUVEC tube formation, and anti-VEGF neutralization","pmids":["12928417"],"confidence":"Medium","gaps":["Signaling pathway from CSF-1R to VEGF induction not defined","In vivo relevance not tested"]},{"year":2004,"claim":"Revealed a viral subversion mechanism in which HIV-1 Nef-activated Hck hijacks the M-CSF receptor complex to blunt signaling.","evidence":"Conditional Nef in TF-1-fms cells, Co-IP, receptor phosphorylation, and proliferation/differentiation assays","pmids":["15626739"],"confidence":"Medium","gaps":["Mechanism of Hck-mediated receptor inhibition not defined","Single cell-line model"]},{"year":2005,"claim":"Positioned M-CSF in the inflammatory osteoclastogenesis cascade between TNF-alpha and RANK induction, and validated receptor blockade therapeutically.","evidence":"TNF-receptor chimeric bone marrow mice, anti-c-Fms blocking antibody, and TRACP 5b resorption marker in arthritis/TNF models","pmids":["16294221"],"confidence":"High","gaps":["Transcriptional mechanism of M-CSF-induced RANK expression not defined"]},{"year":2005,"claim":"Showed CSF1 represses OPG to permit osteoclastogenesis required for tooth eruption, defining a transcriptional regulatory output.","evidence":"CSF-1-deficient tl/tl rats and siRNA knockdown in dental follicle cells with OPG expression readout","pmids":["16109994"],"confidence":"Medium","gaps":["Direct vs. indirect OPG regulation not distinguished","Signaling intermediate to OPG promoter unknown"]},{"year":2006,"claim":"Demonstrated physical and functional coupling of c-Fms with alphaVbeta3 integrin and an adhesion signaling complex in osteoclasts.","evidence":"Anion-exchange chromatography, sequential immunoprecipitation, and co-localization microscopy in osteoclasts","pmids":["16600665"],"confidence":"Medium","gaps":["Functional consequence of cFms-alphaVbeta3 association not directly perturbed","Timing relative to phosphorylation peak unexplained"]},{"year":2009,"claim":"Defined the PLCgamma2/ERK→c-Fos/C/EBPalpha pathway by which M-CSF specifies monocyte lineage in progenitors.","evidence":"Ba/F3-fms and lineage-negative marrow cells with ERK/PLC inhibitors and colony assays","pmids":["19587381"],"confidence":"Medium","gaps":["Inhibitor-based, no genetic confirmation in primary HSPCs","Direct C/EBPalpha-c-Fos interaction not shown"]},{"year":2010,"claim":"Refined the role of ubiquitination, showing c-Cbl-dependent CSF-1R ubiquitination is required for full kinase activation, not just receptor downregulation.","evidence":"CSF-1R mutagenesis (Y559), c-Cbl-deficient macrophages reconstituted with WT vs. ligase-dead C381A Cbl, and SFK inhibitors","pmids":["21041311"],"confidence":"High","gaps":["Structural basis of the proposed kinase-domain conformational change not resolved","Ubiquitin chain topology not defined"]},{"year":2010,"claim":"Distinguished CSF1 from the alternative c-Fms ligand IL-34, showing distinct receptor binding sites and signaling kinetics.","evidence":"Receptor binding competition with distinct blocking MAbs, phosphorylation kinetics, and functional growth/migration assays","pmids":["20489731"],"confidence":"Medium","gaps":["Structural footprints of each ligand on Fms not mapped","Physiological division of labor between ligands not addressed"]},{"year":2012,"claim":"Extended CSF-1R function to the intestinal epithelium, showing it supports Paneth cells and the stem cell niche cell-intrinsically.","evidence":"GI-specific Csf1r knockout, intestinal organoid culture, and stem cell marker immunohistochemistry","pmids":["23314290"],"confidence":"Medium","gaps":["Source of the CSF-1R ligand in this niche not defined","Downstream signaling in Paneth cells not characterized"]},{"year":2013,"claim":"Demonstrated that M-CSF directly instructs myeloid cell fate in single HSCs via PU.1 induction, independent of survival/proliferation selection.","evidence":"Single-cell video imaging, single-cell gene expression, PU.1 reporter, and in vivo M-CSF administration with receptor-deficient controls","pmids":["23575636"],"confidence":"High","gaps":["Signaling intermediates from CSF-1R to PU.1 transcription not mapped","Chromatin mechanism of PU.1 induction unknown"]},{"year":2015,"claim":"Resolved the lipid-signaling sequence underlying M-CSF-induced macropinocytosis in macrophages.","evidence":"Live-cell fluorescent lipid probes with PI3K/PLC/PKC/Ras/Akt inhibitors and macropinocytosis quantification","pmids":["25688212"],"confidence":"Medium","gaps":["Effectors linking DAG/PKC/Ras to actin cup closure not identified","Pharmacology-only dissection"]},{"year":2017,"claim":"Identified lymphatic endothelial cells as an M-CSF source capable of driving pathological osteolysis.","evidence":"LEC-osteoclast co-culture, M-CSF neutralization, Ki20227 inhibition, and intra-tibial LEC injection with micro-CT/ELISA","pmids":["28052488"],"confidence":"Medium","gaps":["Physiological vs. pathological contribution of LEC-derived M-CSF unclear","Single lab"]},{"year":2019,"claim":"Implicated mesothelial cells as a paracrine M-CSF source sustaining peritoneal macrophages.","evidence":"Detection of membrane-bound and secreted CSF1 in mesothelial cells with peritoneal macrophage proximity analysis","pmids":["31251389"],"confidence":"Low","gaps":["Limited methodological detail establishing functional dependence","No genetic source-specific deletion"]},{"year":2023,"claim":"Pinpointed bone marrow Adipoq-lineage progenitors as a dominant physiological source of M-CSF for marrow macrophages and osteoclasts.","evidence":"Adipoq-Cre conditional Csf1 deletion with bone histology, TRAP, flow cytometry, and ovariectomy model; replicated across two studies","pmids":["36779851","36779854"],"confidence":"High","gaps":["Relative contribution versus other stromal sources not fully quantified","Regulation of CSF1 expression in these progenitors not defined"]},{"year":null,"claim":"How CSF-1R signaling output is selectively wired to distinct fates (proliferation vs. differentiation vs. PU.1-driven commitment) across cell types, and the structural basis of ubiquitination-driven kinase activation, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the ubiquitination-induced active CSF-1R conformation","Signaling intermediates from CSF-1R to PU.1 not mapped","Quantitative source hierarchy of CSF1 across tissues incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[3,5,10,13]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,7,22]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[13,19]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[13,19]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,7,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,13,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,7,14]}],"complexes":["cFms-alphaVbeta3 integrin complex (with Pyk2, p130Cas, c-Cbl)"],"partners":["CSF1R","CBL","ITGB3","PTK2B","BCAR1","HCK","IL34"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P09603","full_name":"Macrophage colony-stimulating factor 1","aliases":["Lanimostim","Proteoglycan macrophage colony-stimulating factor","PG-M-CSF"],"length_aa":554,"mass_kda":60.2,"function":"Cytokine that plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. Promotes the release of pro-inflammatory chemokines, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption, and is required for normal bone development. Required for normal male and female fertility. Promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration. 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/8864136","citation_count":32,"is_preprint":false},{"pmid":"15626739","id":"PMC_15626739","title":"HIV-1 Nef interferes with M-CSF receptor signaling through Hck activation and inhibits M-CSF bioactivities.","date":"2004","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15626739","citation_count":32,"is_preprint":false},{"pmid":"12112368","id":"PMC_12112368","title":"GM-CSF and M-CSF modulate beta-chemokine and HIV-1 expression in microglia.","date":"2002","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/12112368","citation_count":31,"is_preprint":false},{"pmid":"31251389","id":"PMC_31251389","title":"Mesothelial cell CSF1 sustains peritoneal macrophage proliferation.","date":"2019","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31251389","citation_count":28,"is_preprint":false},{"pmid":"30120124","id":"PMC_30120124","title":"CSF-1 in Inflammatory and Arthritic Pain Development.","date":"2018","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/30120124","citation_count":28,"is_preprint":false},{"pmid":"8981363","id":"PMC_8981363","title":"Regulation of CSF-1 receptor expression.","date":"1997","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/8981363","citation_count":27,"is_preprint":false},{"pmid":"18378004","id":"PMC_18378004","title":"The selective M-CSF receptor tyrosine kinase inhibitor Ki20227 suppresses experimental autoimmune encephalomyelitis.","date":"2008","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/18378004","citation_count":27,"is_preprint":false},{"pmid":"28834216","id":"PMC_28834216","title":"Beyond the M-CSF receptor - novel therapeutic targets in tumor-associated macrophages.","date":"2017","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/28834216","citation_count":26,"is_preprint":false},{"pmid":"21938481","id":"PMC_21938481","title":"Bisphosphonates modulate the expression of OPG and M-CSF in hMSC-derived osteoblasts.","date":"2011","source":"Clinical oral investigations","url":"https://pubmed.ncbi.nlm.nih.gov/21938481","citation_count":26,"is_preprint":false},{"pmid":"24198819","id":"PMC_24198819","title":"MicroRNA-Mediated Down-Regulation of M-CSF Receptor Contributes to Maturation of Mouse Monocyte-Derived Dendritic Cells.","date":"2013","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24198819","citation_count":26,"is_preprint":false},{"pmid":"36007098","id":"PMC_36007098","title":"Interactions in CSF1-Driven Tenosynovial Giant Cell Tumors.","date":"2022","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/36007098","citation_count":25,"is_preprint":false},{"pmid":"32714570","id":"PMC_32714570","title":"Establishment of bone marrow-derived M-CSF receptor-dependent self-renewing macrophages.","date":"2020","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/32714570","citation_count":25,"is_preprint":false},{"pmid":"23314290","id":"PMC_23314290","title":"The CSF-1 receptor fashions the intestinal stem cell niche.","date":"2012","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/23314290","citation_count":25,"is_preprint":false},{"pmid":"22082370","id":"PMC_22082370","title":"Feedback inhibition of osteoclastogenesis during inflammation by IL-10, M-CSF receptor shedding, and induction of IRF8.","date":"2011","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/22082370","citation_count":25,"is_preprint":false},{"pmid":"21208080","id":"PMC_21208080","title":"M-CSF accelerates orthodontic tooth movement by targeting preosteoclasts in mice.","date":"2011","source":"The Angle orthodontist","url":"https://pubmed.ncbi.nlm.nih.gov/21208080","citation_count":24,"is_preprint":false},{"pmid":"8100809","id":"PMC_8100809","title":"M-CSF gene transduction in multidrug-resistant human cancer cells to enhance anti-P-glycoprotein antibody-dependent macrophage-mediated cytotoxicity.","date":"1993","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/8100809","citation_count":23,"is_preprint":false},{"pmid":"30528455","id":"PMC_30528455","title":"Concomitant type I IFN and M-CSF signaling reprograms monocyte differentiation and drives pro-tumoral arginase production.","date":"2018","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/30528455","citation_count":22,"is_preprint":false},{"pmid":"24748497","id":"PMC_24748497","title":"M-CSF inhibits anti-HIV-1 activity of IL-32, but they enhance M2-like phenotypes of macrophages.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24748497","citation_count":22,"is_preprint":false},{"pmid":"16600665","id":"PMC_16600665","title":"M-CSF induces the stable interaction of cFms with alphaVbeta3 integrin in osteoclasts.","date":"2006","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16600665","citation_count":22,"is_preprint":false},{"pmid":"8981359","id":"PMC_8981359","title":"CSF-1 and cell cycle control in macrophages.","date":"1997","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/8981359","citation_count":21,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49838,"output_tokens":6182,"usd":0.121122,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14950,"output_tokens":6219,"usd":0.115113,"stage2_stop_reason":"end_turn"},"total_usd":0.236235,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"CSF-1 activation of CSF-1R causes Cbl tyrosine phosphorylation, Cbl-CSF-1R association, and their simultaneous multiubiquitination at the plasma membrane, leading to rapid CSF-1R internalization and degradation. Cbl-/- macrophages fail to exhibit CSF-1R multiubiquitination and show slower CSF-1R internalization, demonstrating that Cbl positively regulates coordinated CSF-1R multiubiquitination and endocytosis to attenuate proliferative signaling.\",\n      \"method\": \"Gene-targeted knockout macrophages (Cbl-/-), Co-immunoprecipitation, ubiquitination assay, receptor internalization assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic KO with defined mechanistic readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"10393178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CSF-1R phospho-Tyr-559 is required for binding of Src family kinases (SFKs), and this site is both necessary and sufficient for CSF-1-induced CSF-1R ubiquitination and tyrosine phosphorylation. c-Cbl-mediated CSF-1R ubiquitination (dependent on its E3 ligase activity) is required for a conformational change in the kinase domain enabling amplification of receptor tyrosine phosphorylation and full receptor activation.\",\n      \"method\": \"Site-directed mutagenesis of CSF-1R, c-Cbl-deficient macrophages, reconstitution with wild-type vs. ubiquitin ligase-dead C381A c-Cbl, SFK inhibitors\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with mutagenesis, genetic KO, and pharmacological inhibition as orthogonal methods\",\n      \"pmids\": [\"21041311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"M-CSF induces phosphorylation of transcription factors Mitf and TFE3 via a conserved MAPK consensus site, triggering recruitment of the coactivator p300. An unphosphorylatable mutant at this MAPK serine specifically fails to support formation of multinucleated osteoclasts, linking M-CSF/MAPK signaling to Mitf/TFE3 phosphorylation as a nuclear target required for osteoclast maturation.\",\n      \"method\": \"Phosphorylation assay, co-immunoprecipitation with p300, site-directed mutagenesis, cell differentiation assay in Mitf(mi/mi) osteoclasts\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis, co-IP, and functional differentiation assay with genetic mutant model, multiple orthogonal methods\",\n      \"pmids\": [\"11684011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"M-CSF directly induces expression of the myeloid master regulator PU.1 in single hematopoietic stem cells (HSCs) and instructs myeloid cell-fate change independently of selective survival or proliferation. In vivo, high systemic M-CSF drives M-CSF-receptor-dependent activation of endogenous PU.1 protein in single HSCs, causing a PU.1-dependent myeloid differentiation preference.\",\n      \"method\": \"Single-cell video imaging, single-cell gene expression analysis, PU.1 promoter reporter assay, in vivo M-CSF administration in mice, M-CSF receptor-deficient controls\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (single-cell imaging, reporter assay, in vivo genetic model), independently validated in vitro and in vivo\",\n      \"pmids\": [\"23575636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"M-CSF, TNF-alpha, and RANKL promote osteoclast survival through convergent signaling on mTOR/S6 kinase. M-CSF signals to Akt, and inhibition of PI3K, Akt, ERKs, geranylgeranylated proteins, or mTOR/S6K induces osteoclast apoptosis. mTOR regulates protein translation via S6K, 4E-BP1, and S6, and inhibition of translation by other mechanisms also induces osteoclast apoptosis.\",\n      \"method\": \"Pharmacological inhibition (rapamycin, PI3K inhibitors, ERK inhibitors), S6K phosphorylation assay, apoptosis assay, in vitro bone resorption assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with multiple inhibitors, single lab, functional apoptosis and resorption readouts\",\n      \"pmids\": [\"14502240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TNF-alpha stimulates M-CSF gene expression in stromal cells via TNF-responsive stromal cells, and M-CSF in turn induces RANK expression in osteoclast precursors. Antibody blockade of the M-CSF receptor c-Fms selectively and completely arrested pathological osteoclastogenesis and bone resorption in inflammatory arthritis and TNF-injected mice.\",\n      \"method\": \"Chimeric bone marrow transplant mice (TNF receptor-deficient stromal vs. precursor cells), anti-c-Fms blocking antibody in vivo, TRACP 5b bone resorption marker measurement\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic chimera approach, receptor blockade, multiple in vivo readouts establishing pathway position of M-CSF between TNF-alpha and RANK induction\",\n      \"pmids\": [\"16294221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"M-CSF neutralization in vivo completely prevents the rise in osteoclast number, increase in bone resorption, and bone loss induced by ovariectomy. Estrogen deficiency induces M-CSF production through an Egr-1-dependent mechanism; Egr-1-deficient mice with maximally stimulated stromal M-CSF production show increased bone resorption reversed by anti-M-CSF antibody.\",\n      \"method\": \"In vivo M-CSF neutralizing antibody, ovariectomy model, Egr-1 knockout mice, bone resorption and mass measurements\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO combined with neutralizing antibody, multiple in vivo bone phenotype readouts, epistatic placement of Egr-1 upstream of M-CSF\",\n      \"pmids\": [\"10792003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"M-CSF preferentially activates PLCgamma2 and thereby ERK to stabilize c-Fos and stimulate C/EBPalpha(S21) phosphorylation in myeloid progenitors, favoring monocyte lineage commitment. ERK inhibition prevented M-CSF-induced c-Fos induction, reduced C/EBPalpha phosphorylation, and decreased colony-forming unit-monocytes, establishing a mechanistic pathway from M-CSF receptor to monocyte specification.\",\n      \"method\": \"Receptor-expressing Ba/F3 cells, lineage-negative murine marrow cells, ERK inhibitors, PLC inhibitors, colony assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection with multiple pathway inhibitors, functional colony assay, single lab\",\n      \"pmids\": [\"19587381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CSF-1R autophosphorylation site Y807 is essential for the differentiation signal: its mutation completely abrogates differentiation and conversely increases M-CSF-dependent proliferation, suggesting Y807 controls a switch between growth and differentiation. Sites Y697, Y706, and Y721 in the kinase insert region augment but are not required for differentiation.\",\n      \"method\": \"Site-directed mutagenesis of CSF-1R tyrosine sites, expression in FDC-P1 myeloid cells, differentiation and proliferation assays\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with functional differentiation/proliferation readout, single lab\",\n      \"pmids\": [\"8981370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"M-CSF-induced macropinocytosis in macrophages proceeds through a sequential PI3K → PLC → DAG → PKC/Ras pathway. PIP3 (PI3K product) appears in cups prior to DAG; PLC inhibitor blocks M-CSF-induced but not PMA-induced macropinocytosis; Ras and PKC inhibitors block both. Akt inhibition does not block macropinocytosis despite Akt activation by M-CSF.\",\n      \"method\": \"Live-cell fluorescent lipid probes, pharmacological inhibitors (PI3K, PLC, PKC, Ras, Akt), macropinocytosis quantification\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal pharmacological inhibitors, live imaging, single lab\",\n      \"pmids\": [\"25688212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-34 and M-CSF share the Fms receptor but differ in receptor binding domains, signal activation kinetics, and downstream biological activities. IL-34 induces stronger but more transient tyrosine phosphorylation of Fms and downstream molecules and more rapidly downregulates Fms. An anti-Fms MAb blocked both IL-34-Fms and M-CSF-Fms binding, but another MAb blocked only M-CSF-Fms binding, indicating distinct binding sites on Fms.\",\n      \"method\": \"Receptor binding competition assay with blocking MAbs, phosphorylation kinetics assay, cell growth/survival assay, migration assay, morphological analysis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor binding competition with distinct MAbs, phosphorylation kinetics, multiple functional readouts, single lab\",\n      \"pmids\": [\"20489731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"M-CSF induces stable association of the M-CSF receptor cFms with alphaVbeta3 integrin in osteoclasts. The cFms-alphaVbeta3 complex also contains Pyk2, p130Cas, and c-Cbl. Association is induced by M-CSF but peaks after the peak of cFms tyrosine phosphorylation. Co-localization of both receptors occurs in the podosomal actin ring during adhesion on glass but not in the sealing zone on bone.\",\n      \"method\": \"Anion-exchange chromatography, sequential immunoprecipitation, co-localization by microscopy in osteoclasts\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — sequential purification and Co-IP, co-localization imaging, single lab\",\n      \"pmids\": [\"16600665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HIV-1 Nef interferes with the M-CSF/M-CSF receptor signaling pathway through Hck activation. Nef-activated Hck constitutively associates with the M-CSF receptor complex, causing markedly diminished tyrosine phosphorylation/activation of the M-CSF receptor in response to M-CSF and consequent inhibition of M-CSF-mediated proliferation and macrophage differentiation.\",\n      \"method\": \"Conditionally active Nef construct in TF-1-fms myeloid cells, receptor tyrosine phosphorylation assay, co-immunoprecipitation, proliferation and differentiation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of Nef-Hck-receptor complex, phosphorylation assay, functional proliferation/differentiation readout, single lab\",\n      \"pmids\": [\"15626739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CSF-1 is expressed as a secreted glycoprotein, proteoglycan (circulating or matrix-bound), or biologically active cell-surface glycoprotein. A 3.13-kb CSF-1 promoter/first intron driving the membrane-spanning CSF-1 precursor transgene rescues all gross phenotypic defects of Csf1-null op/op mice, identifying new cellular sites of CSF-1 expression including ovarian granulosa cells, mammary ductal epithelium, testicular Leydig cells, serous acinar cells, and Paneth cells.\",\n      \"method\": \"Transgenic rescue of Csf1(op)/Csf1(op) null mice, lacZ reporter under same promoter, tissue CSF-1 protein measurements, hematopoietic parameter analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic rescue with comprehensive phenotypic and molecular characterization, multiple tissues examined\",\n      \"pmids\": [\"11418465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"M-CSF induces VEGF production and release from human monocytes in a dose-dependent manner. VEGF released by M-CSF-stimulated monocytes is biologically active as it induces tube formation in HUVECs, an effect blocked by anti-VEGF antibody.\",\n      \"method\": \"Human monocyte culture with recombinant M-CSF, VEGF ELISA, HUVEC tube formation assay, antibody neutralization\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional VEGF activity assay with antibody neutralization, dose-response, single lab\",\n      \"pmids\": [\"12928417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Bone marrow Adipoq-lineage progenitors (but not mature adipocytes) are a major cellular source of M-CSF in bone marrow, expressing CSF1 at much higher levels than osteoblast lineage cells. Cell-specific deletion of Csf1 in Adipoq-lineage progenitors drastically reduces bone marrow macrophage and osteoclast generation, causing severe osteopetrosis, and significantly alleviates ovariectomy-induced osteoporosis.\",\n      \"method\": \"Cell-specific conditional knockout (Adipoq-Cre), bone histology, TRAP staining, flow cytometry, bone mass measurement, ovariectomy model\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple phenotypic readouts, comparison across multiple cell-type-specific deletions, replicated in two independent studies (PMID 36779851 and 36779854)\",\n      \"pmids\": [\"36779851\", \"36779854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Lymphatic endothelial cells (LECs) produce high levels of M-CSF (but not RANKL, IL-6, or TNF), and LEC-mediated osteoclast formation and bone resorption are blocked by an M-CSF neutralizing antibody or M-CSF receptor inhibitor Ki20227. Intra-tibial LEC injection in mice causes massive osteolysis with elevated serum and bone marrow M-CSF, reversed by Ki20227 treatment.\",\n      \"method\": \"LEC-osteoclast co-culture, M-CSF neutralizing antibody, Ki20227 pharmacological inhibition, intra-tibial LEC injection mouse model, micro-CT, ELISA\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody neutralization and pharmacological blockade with in vitro and in vivo readouts, single lab\",\n      \"pmids\": [\"28052488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CSF-1R (expressed primarily on Paneth cells) directly supports Paneth cell maturation and thereby fashions the intestinal stem cell niche. GI-specific Csf1r deletion in young adult mice leads to Paneth cell loss, changed distribution of proliferating cells, and loss of Lgr5 and other stem cell marker expression. Csf1r-/- crypts in organoid culture show the Paneth cell defect is epithelial cell-intrinsic and affects stem cell activity.\",\n      \"method\": \"Conditional Csf1r knockout (GI-specific), intestinal organoid culture, immunohistochemistry for stem cell markers, 3D localization of CSF-1R\",\n      \"journal\": \"Stem cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with organoid culture validation, multiple stem cell marker readouts, single lab\",\n      \"pmids\": [\"23314290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CSF-1 promotes neuronal survival and process outgrowth in vitro in a dose-dependent manner. Both CSF-1 and its receptor are expressed in developing mouse brain. CSF-1-null op/op mice exhibit abnormal brainstem auditory and visual evoked potentials and aberrant cortical neuronal function; daily CSF-1 injection of postnatal op/op mice largely rescues these neurological abnormalities.\",\n      \"method\": \"Neuronal culture with CSF-1 treatment, nuclease protection assay for CSF-1/receptor expression, electrophysiological assays (evoked potentials, intracortical recordings), in vivo CSF-1 rescue injections in op/op mice\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional assay plus in vivo rescue experiment, multiple electrophysiological readouts, single lab\",\n      \"pmids\": [\"8787741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mesothelial cells produce both membrane-bound and secreted CSF1 that sustain peritoneal macrophage proliferation and growth. Peritoneal macrophages are found in close proximity to mesothelial cells in the peritoneal cavity.\",\n      \"method\": \"CSF1 protein detection in mesothelial cells (membrane and secreted forms), peritoneal macrophage localization, co-culture/proximity analysis\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic detail in abstract regarding methods used to establish functional dependence\",\n      \"pmids\": [\"31251389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CSF-1 down-regulates OPG gene expression in dental follicle cells in vivo, enabling osteoclastogenesis required for tooth eruption. CSF-1-deficient toothless (tl/tl) rats show higher OPG expression in dental follicle than normal littermates; siRNA knockdown of CSF-1 mRNA in dental follicle cells causes OPG upregulation.\",\n      \"method\": \"Comparison of OPG expression in CSF-1-deficient vs. normal rats, siRNA knockdown of CSF-1 in dental follicle cells, OPG gene expression analysis\",\n      \"journal\": \"Journal of dental research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic deficiency model plus siRNA knockdown, two orthogonal approaches establishing CSF-1 regulation of OPG\",\n      \"pmids\": [\"16109994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"M-CSF activates Fms tyrosine kinase, which sequentially activates PI3K or PLCgamma, leading to activation of the small GTPase Rac, which regulates actin cytoskeletal reorganization in microglia. Iba1 (a macrophage/microglia-specific calcium-binding protein) is involved in the Rac signaling pathway downstream of M-CSF/PLCgamma.\",\n      \"method\": \"Intracellular signaling analysis in microglia, pathway inhibition/activation studies (described as review with experimental basis)\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review-style abstract summarizing experimental findings but limited methodological detail; single lab\",\n      \"pmids\": [\"12379904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Smooth muscle cells from arteriosclerotic lesions express the M-CSF receptor c-fms and exhibit high-affinity M-CSF binding, unlike normal medial smooth muscle cells. M-CSF stimulation of these intimal smooth muscle cells causes tyrosine phosphorylation and increased cell proliferation.\",\n      \"method\": \"c-fms expression analysis, M-CSF binding assay, anti-phosphotyrosine immunoblot, cell proliferation assay, immunocytochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding assay, phosphorylation assay, and proliferation assay in primary cells, single lab\",\n      \"pmids\": [\"1531986\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CSF1 (M-CSF) is a homodimeric cytokine that signals exclusively through its receptor tyrosine kinase CSF-1R (c-Fms) by inducing receptor dimerization, transphosphorylation at multiple intracellular tyrosine residues (notably Y559, Y721, Y807), and sequential activation of SFK/c-Cbl-mediated receptor ubiquitination required for full kinase activation; downstream it engages PI3K/Akt/mTOR, PLCgamma/ERK, and Rac/actin pathways to drive survival, proliferation, chemotaxis, and differentiation of monocytes, macrophages, osteoclasts, microglia, and dendritic cells, while also directly instructing myeloid lineage commitment in hematopoietic stem cells by inducing PU.1, and is produced locally by mesenchymal/stromal cells (including bone marrow Adipoq-lineage progenitors, mesothelial cells, smooth muscle cells, and endothelial cells) to regulate tissue-resident macrophage populations in a paracrine fashion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CSF1 (M-CSF) is a stromal-derived cytokine that drives the survival, proliferation, differentiation, and lineage commitment of myeloid cells by activating its receptor tyrosine kinase CSF-1R (c-Fms) [#3, #5]. Receptor activation is gated by an ubiquitin-dependent amplification loop: CSF-1R phospho-Tyr-559 recruits Src family kinases, and c-Cbl-mediated, E3-ligase-dependent receptor ubiquitination drives a kinase-domain conformational change required for full receptor tyrosine phosphorylation, while the same Cbl-coordinated multiubiquitination also triggers receptor internalization and degradation to attenuate signaling [#0, #1]. The activated receptor branches into PI3K/Akt/mTOR-S6K signaling that sustains cell survival and translation [#4], a PLCgamma2/ERK arm that stabilizes c-Fos and phosphorylates C/EBPalpha to specify monocyte commitment [#7], and a PI3K\\u2192PLC\\u2192DAG\\u2192PKC/Ras cascade and Rac-dependent actin remodeling that govern macropinocytosis and cytoskeletal reorganization [#9]. A distinct CSF-1R autophosphorylation site, Y807, acts as a switch between proliferation and differentiation [#8]. In the nucleus, M-CSF/MAPK signaling phosphorylates Mitf/TFE3 to recruit p300 and enable osteoclast maturation [#2], and at the level of stem cells M-CSF directly induces the master regulator PU.1 to instruct myeloid fate in single hematopoietic stem cells [#3]. CSF1 is produced as secreted, proteoglycan, and cell-surface forms by diverse stromal sources \\u2014 bone marrow Adipoq-lineage progenitors, lymphatic and other endothelial cells, mesothelial cells, and intimal smooth muscle cells \\u2014 to sustain tissue-resident macrophage and osteoclast populations in a paracrine manner [#13, #15, #16], and it is a central effector in pathological bone resorption, linking TNF-alpha and estrogen-deficiency signals to osteoclastogenesis [#5, #6]. Beyond myeloid biology, CSF-1R supports Paneth cell maturation and the intestinal stem cell niche [#17] and promotes neuronal survival and function during brain development [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established that CSF1 acts through c-Fms beyond classical myeloid targets, showing pathologically altered cells can acquire receptor responsiveness.\",\n      \"evidence\": \"c-fms expression, M-CSF binding, phosphotyrosine immunoblot and proliferation assays in arteriosclerotic intimal smooth muscle cells\",\n      \"pmids\": [\"1531986\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define downstream signaling branches engaged in smooth muscle cells\", \"Mechanism of ectopic c-fms induction unresolved\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Extended CSF1 function into the nervous system, demonstrating a non-myeloid trophic role in vivo.\",\n      \"evidence\": \"Neuronal culture survival/outgrowth assays, expression analysis, evoked-potential electrophysiology, and CSF-1 rescue injection in op/op mice\",\n      \"pmids\": [\"8787741\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. microglia-mediated neuronal effect not separated\", \"Receptor-bearing cell type mediating rescue not defined\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Mapped the growth-versus-differentiation decision to a specific receptor autophosphorylation site, defining a molecular switch.\",\n      \"evidence\": \"Site-directed mutagenesis of CSF-1R tyrosines in FDC-P1 cells with differentiation/proliferation readouts\",\n      \"pmids\": [\"8981370\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effector bound at Y807 not identified\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified Cbl as the coordinator of CSF-1R ubiquitination and endocytosis, defining the negative-feedback arm of signaling.\",\n      \"evidence\": \"Cbl-/- macrophages, reciprocal Co-IP, ubiquitination and receptor internalization assays\",\n      \"pmids\": [\"10393178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not yet show ubiquitination is required for receptor activation (later refined)\", \"Specific lysines ubiquitinated not mapped\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Placed CSF1 epistatically downstream of estrogen-deficiency signaling in bone loss, establishing it as a required mediator of osteoclastogenesis.\",\n      \"evidence\": \"In vivo M-CSF neutralizing antibody and Egr-1 knockout mice in an ovariectomy model with bone resorption/mass readouts\",\n      \"pmids\": [\"10792003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stromal cell type producing M-CSF not defined\", \"Direct Egr-1 binding to the Csf1 promoter not shown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined a nuclear endpoint of M-CSF/MAPK signaling required for osteoclast maturation.\",\n      \"evidence\": \"Phosphorylation assays, p300 Co-IP, mutagenesis of a MAPK serine, and differentiation assays in Mitf(mi/mi) osteoclasts\",\n      \"pmids\": [\"11684011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase phosphorylating Mitf/TFE3 not identified\", \"Target genes driven by p300 recruitment not enumerated\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the molecular forms and tissue sources of CSF1 and proved the membrane-spanning precursor is sufficient to rescue the null phenotype.\",\n      \"evidence\": \"Transgenic rescue of Csf1(op)/op mice with a precursor transgene plus lacZ reporter and tissue protein measurements\",\n      \"pmids\": [\"11418465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative functional contributions of secreted vs. membrane forms not dissected\", \"Cell-autonomous requirement at each new site not tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Outlined the Fms\\u2192PI3K/PLCgamma\\u2192Rac\\u2192actin axis governing microglial cytoskeletal responses.\",\n      \"evidence\": \"Signaling/pathway analysis in microglia (review-style with experimental basis)\",\n      \"pmids\": [\"12379904\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Review-style abstract with limited methodological detail\", \"Iba1 role in the pathway not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapped M-CSF survival signaling to convergent mTOR/S6K-dependent translation control in osteoclasts.\",\n      \"evidence\": \"Pharmacological inhibition of PI3K/Akt/ERK/mTOR with apoptosis and bone resorption assays\",\n      \"pmids\": [\"14502240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Inhibitor-based dissection without genetic confirmation\", \"Convergence point of M-CSF, TNF, RANKL not molecularly defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that M-CSF instructs macrophages to secrete biologically active VEGF, linking the cytokine to angiogenesis.\",\n      \"evidence\": \"Human monocyte culture, VEGF ELISA, HUVEC tube formation, and anti-VEGF neutralization\",\n      \"pmids\": [\"12928417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway from CSF-1R to VEGF induction not defined\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealed a viral subversion mechanism in which HIV-1 Nef-activated Hck hijacks the M-CSF receptor complex to blunt signaling.\",\n      \"evidence\": \"Conditional Nef in TF-1-fms cells, Co-IP, receptor phosphorylation, and proliferation/differentiation assays\",\n      \"pmids\": [\"15626739\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Hck-mediated receptor inhibition not defined\", \"Single cell-line model\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Positioned M-CSF in the inflammatory osteoclastogenesis cascade between TNF-alpha and RANK induction, and validated receptor blockade therapeutically.\",\n      \"evidence\": \"TNF-receptor chimeric bone marrow mice, anti-c-Fms blocking antibody, and TRACP 5b resorption marker in arthritis/TNF models\",\n      \"pmids\": [\"16294221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional mechanism of M-CSF-induced RANK expression not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed CSF1 represses OPG to permit osteoclastogenesis required for tooth eruption, defining a transcriptional regulatory output.\",\n      \"evidence\": \"CSF-1-deficient tl/tl rats and siRNA knockdown in dental follicle cells with OPG expression readout\",\n      \"pmids\": [\"16109994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect OPG regulation not distinguished\", \"Signaling intermediate to OPG promoter unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated physical and functional coupling of c-Fms with alphaVbeta3 integrin and an adhesion signaling complex in osteoclasts.\",\n      \"evidence\": \"Anion-exchange chromatography, sequential immunoprecipitation, and co-localization microscopy in osteoclasts\",\n      \"pmids\": [\"16600665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of cFms-alphaVbeta3 association not directly perturbed\", \"Timing relative to phosphorylation peak unexplained\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the PLCgamma2/ERK\\u2192c-Fos/C/EBPalpha pathway by which M-CSF specifies monocyte lineage in progenitors.\",\n      \"evidence\": \"Ba/F3-fms and lineage-negative marrow cells with ERK/PLC inhibitors and colony assays\",\n      \"pmids\": [\"19587381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Inhibitor-based, no genetic confirmation in primary HSPCs\", \"Direct C/EBPalpha-c-Fos interaction not shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Refined the role of ubiquitination, showing c-Cbl-dependent CSF-1R ubiquitination is required for full kinase activation, not just receptor downregulation.\",\n      \"evidence\": \"CSF-1R mutagenesis (Y559), c-Cbl-deficient macrophages reconstituted with WT vs. ligase-dead C381A Cbl, and SFK inhibitors\",\n      \"pmids\": [\"21041311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the proposed kinase-domain conformational change not resolved\", \"Ubiquitin chain topology not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Distinguished CSF1 from the alternative c-Fms ligand IL-34, showing distinct receptor binding sites and signaling kinetics.\",\n      \"evidence\": \"Receptor binding competition with distinct blocking MAbs, phosphorylation kinetics, and functional growth/migration assays\",\n      \"pmids\": [\"20489731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural footprints of each ligand on Fms not mapped\", \"Physiological division of labor between ligands not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended CSF-1R function to the intestinal epithelium, showing it supports Paneth cells and the stem cell niche cell-intrinsically.\",\n      \"evidence\": \"GI-specific Csf1r knockout, intestinal organoid culture, and stem cell marker immunohistochemistry\",\n      \"pmids\": [\"23314290\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Source of the CSF-1R ligand in this niche not defined\", \"Downstream signaling in Paneth cells not characterized\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that M-CSF directly instructs myeloid cell fate in single HSCs via PU.1 induction, independent of survival/proliferation selection.\",\n      \"evidence\": \"Single-cell video imaging, single-cell gene expression, PU.1 reporter, and in vivo M-CSF administration with receptor-deficient controls\",\n      \"pmids\": [\"23575636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling intermediates from CSF-1R to PU.1 transcription not mapped\", \"Chromatin mechanism of PU.1 induction unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the lipid-signaling sequence underlying M-CSF-induced macropinocytosis in macrophages.\",\n      \"evidence\": \"Live-cell fluorescent lipid probes with PI3K/PLC/PKC/Ras/Akt inhibitors and macropinocytosis quantification\",\n      \"pmids\": [\"25688212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effectors linking DAG/PKC/Ras to actin cup closure not identified\", \"Pharmacology-only dissection\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified lymphatic endothelial cells as an M-CSF source capable of driving pathological osteolysis.\",\n      \"evidence\": \"LEC-osteoclast co-culture, M-CSF neutralization, Ki20227 inhibition, and intra-tibial LEC injection with micro-CT/ELISA\",\n      \"pmids\": [\"28052488\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological vs. pathological contribution of LEC-derived M-CSF unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Implicated mesothelial cells as a paracrine M-CSF source sustaining peritoneal macrophages.\",\n      \"evidence\": \"Detection of membrane-bound and secreted CSF1 in mesothelial cells with peritoneal macrophage proximity analysis\",\n      \"pmids\": [\"31251389\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Limited methodological detail establishing functional dependence\", \"No genetic source-specific deletion\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Pinpointed bone marrow Adipoq-lineage progenitors as a dominant physiological source of M-CSF for marrow macrophages and osteoclasts.\",\n      \"evidence\": \"Adipoq-Cre conditional Csf1 deletion with bone histology, TRAP, flow cytometry, and ovariectomy model; replicated across two studies\",\n      \"pmids\": [\"36779851\", \"36779854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution versus other stromal sources not fully quantified\", \"Regulation of CSF1 expression in these progenitors not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CSF-1R signaling output is selectively wired to distinct fates (proliferation vs. differentiation vs. PU.1-driven commitment) across cell types, and the structural basis of ubiquitination-driven kinase activation, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the ubiquitination-induced active CSF-1R conformation\", \"Signaling intermediates from CSF-1R to PU.1 not mapped\", \"Quantitative source hierarchy of CSF1 across tissues incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [3, 5, 10, 13]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 7, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [13, 19]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [13, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 7, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 13, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 7, 14]}\n    ],\n    \"complexes\": [\"cFms-alphaVbeta3 integrin complex (with Pyk2, p130Cas, c-Cbl)\"],\n    \"partners\": [\"CSF1R\", \"CBL\", \"ITGB3\", \"PTK2B\", \"BCAR1\", \"HCK\", \"IL34\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}