Interleukin-34 (IL34) is a secreted homodimeric four-helix-bundle cytokine that functions as a tissue-restricted agonist of the macrophage colony-stimulating factor 1 receptor (CSF1R). Produced predominantly by epidermal keratinocytes and central nervous system neurons, IL34 binds the N-terminal immunoglobulin-like domains of CSF1R to induce receptor dimerization and activation of downstream CSF1R signaling, including ERK1/2 phosphorylation in monocytes. Through CSF1R signaling, IL34 promotes the survival, proliferation, chemotaxis, and differentiation of monocytes, tissue macrophages, epidermal Langerhans cells, and brain microglia, and also interacts with syndecan-1 (SDC1) and receptor-type tyrosine-protein phosphatase zeta (PTPRZ1) at the cell surface.
Definition: Any process that activates or increases the frequency, rate or extent of microglial cell proliferation.
Justification: Extrinsic secreted cytokines such as neuron-derived IL34 (and CSF1) act via CSF1R to stimulate microglial cell proliferation rather than executing the cell-autonomous microglial division process directly. GO currently provides microglial cell proliferation (GO:0061518), positive regulation of macrophage proliferation (GO:0120041), and positive regulation of glial cell proliferation (GO:0060252, along with lineage-specific terms such as positive regulation of astrocyte proliferation, GO:0048711), but lacks a specific positive regulation term for microglial cell proliferation (which should be placed under both GO:0120041 and GO:0060252).
Parent term: positive regulation of macrophage proliferation
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001934 positive regulation of protein phosphorylation | IDA PMID:18467591 Discovery of a cytokine and its receptor by functional scree... | KEEP AS NON CORE | Summary: Recombinant human IL34 stimulates tyrosine phosphorylation of CSF1R and phosphorylation of ERK1/2 (MAPK1/MAPK3) in primary human monocytes. Reason: Directly supported by biochemical assays in PMID:18467591 showing rapid CSF1R and ERK1/2 phosphorylation in human monocytes upon IL34 stimulation. Retained as non-core because intracellular protein phosphorylation is a downstream consequence of CSF1R activation rather than a direct catalytic activity of the secreted cytokine. Supporting Evidence: PMID:18467591 One of the highly selective proteins was a previously undescribed ligand, designated interleukin-34 (IL-34), which stimulates monocyte viability but does not affect responses in a wide spectrum of other assays. In a separate functional screen, we used a collection of extracellular domains of transmembrane proteins to discover the receptor for IL-34, which was a known cytokine receptor, colony-stimulating factor 1 (also called macrophage colony-stimulating factor) receptor. Reactome:R-HSA-6787820 Like CSF1, IL34 stimulation of CSF1R leads to phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2 in human monocytes (Lin et al. 2008). |
| GO:0005157 macrophage colony-stimulating factor receptor binding | IBA GO_REF:0000033 | MODIFY | Summary: Phylogenetic propagation from PANTHER node PTN002823014 (seeded by human IL34, Q6ZMJ4) captures CSF1R binding but omits IL34's agonist activity as a signaling cytokine. Replace with GO:0005125 (cytokine activity). Reason: IL34 is not an inert CSF1R binder; it is a secreted four-helix-bundle cytokine agonist that engages CSF1R to trigger receptor dimerization and intracellular signaling (PMID:18467591, PMID:22483114). In the GO molecular function hierarchy, GO:0005157 (macrophage colony-stimulating factor receptor binding) sits under GO:0005102 (signaling receptor binding) rather than GO:0048018 (receptor ligand activity), so annotating only GO:0005157 misses the ligand's signaling agonist activity. Upgrading to GO:0005125 (cytokine activity, an is_a child of GO:0048018 receptor ligand activity) accurately captures IL34's core molecular function. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN002823014 Β· IL34 ancestral node SUPPORTS TRANSFER Node PTN002823014 is seeded by human IL34 (Q6ZMJ4); the biology transfers across vertebrate IL34 orthologs, and the refinement is from receptor binding (GO:0005157) to cytokine agonist activity (GO:0005125). UniProtKB:Q6ZMJ4 Β· human IL34 SUPPORTS TRANSFER Self-seeded by human IL34 experimental evidence (PMID:18467591). Proposed replacements: cytokine activity Supporting Evidence: PMID:18467591 One of the highly selective proteins was a previously undescribed ligand, designated interleukin-34 (IL-34), which stimulates monocyte viability but does not affect responses in a wide spectrum of other assays. In a separate functional screen, we used a collection of extracellular domains of transmembrane proteins to discover the receptor for IL-34, which was a known cytokine receptor, colony-stimulating factor 1 (also called macrophage colony-stimulating factor) receptor. Reactome:R-HSA-6787820 Like CSF1, IL34 stimulation of CSF1R leads to phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2 in human monocytes (Lin et al. 2008). |
| GO:0005157 macrophage colony-stimulating factor receptor binding | IDA PMID:18467591 Discovery of a cytokine and its receptor by functional scree... | MODIFY | Summary: PMID:18467591 demonstrated both direct binding of IL34 to CSF1R and potent cytokine agonist activity on primary human monocytes and bone marrow progenitors. Upgrade to GO:0005125 (cytokine activity). Reason: Consistent with the IBA and IEA rows for GO:0005157: PMID:18467591 established IL34 as a functional cytokine ligand that binds CSF1R and activates downstream signaling to control myeloid survival and differentiation. Replacing receptor binding (GO:0005157) with cytokine activity (GO:0005125, under GO:0048018 receptor ligand activity) captures the agonist molecular function demonstrated in this study. Proposed replacements: cytokine activity Supporting Evidence: PMID:18467591 One of the highly selective proteins was a previously undescribed ligand, designated interleukin-34 (IL-34), which stimulates monocyte viability but does not affect responses in a wide spectrum of other assays. In a separate functional screen, we used a collection of extracellular domains of transmembrane proteins to discover the receptor for IL-34, which was a known cytokine receptor, colony-stimulating factor 1 (also called macrophage colony-stimulating factor) receptor. Reactome:R-HSA-6787820 Like CSF1, IL34 stimulation of CSF1R leads to phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2 in human monocytes (Lin et al. 2008). |
| GO:0005157 macrophage colony-stimulating factor receptor binding | IEA GO_REF:0000002 | MODIFY | Summary: Automated InterPro2GO mapping from IPR020415 (Interleukin-34). Replace with GO:0005125 (cytokine activity) for consistency with the experimental and phylogenetic annotations. Reason: All members of the IL34 family (IPR020415 / PTHR28606) act as secreted cytokine agonists of CSF1R. Replacing GO:0005157 with GO:0005125 (cytokine activity) maintains action consistency across all GO:0005157 rows and captures receptor ligand activity. Proposed replacements: cytokine activity Supporting Evidence: PMID:18467591 One of the highly selective proteins was a previously undescribed ligand, designated interleukin-34 (IL-34), which stimulates monocyte viability but does not affect responses in a wide spectrum of other assays. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Uninformative generic protein binding annotation from a high-throughput yeast two-hybrid screen (HuRI). Reason: Bare GO:0005515 (protein binding) is uninformative and does not describe IL34's molecular function as a secreted cytokine ligand. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: IL34 is a secreted glycoprotein with an N-terminal signal peptide (aa 1-20) that acts in the extracellular region. Reason: Phylogenetic inference from PTN002823014 is directly supported by experimental secretion assays in PMID:18467591. Supporting Evidence: file:human/IL34/IL34-uniprot.txt CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:18467591}. PMID:30066957 IL-34 is synthesized as a secreted homodimeric glycoprotein that binds to the extracellular domains of CSF-1R |
| GO:0005576 extracellular region | IDA PMID:18467591 Discovery of a cytokine and its receptor by functional scree... | ACCEPT | Summary: Direct experimental evidence demonstrating that human IL34 is secreted into the extracellular medium as a homodimeric glycoprotein. Reason: Core subcellular location where mature IL34 functions to engage cell-surface receptors. Supporting Evidence: file:human/IL34/IL34-uniprot.txt CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:18467591}. PMID:30066957 IL-34 is synthesized as a secreted homodimeric glycoprotein that binds to the extracellular domains of CSF-1R |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: Automated localization mapping consistent with experimental evidence that IL34 is secreted into the extracellular region. Reason: Consistent with IBA and IDA annotations for GO:0005576. Supporting Evidence: file:human/IL34/IL34-uniprot.txt CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:18467591}. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-448632 | ACCEPT | Summary: Reactome reaction assertion for noncovalent homodimerization of secreted IL34 in the extracellular region. Reason: Consistent with experimental evidence that IL34 forms a secreted homodimer in the extracellular region. Supporting Evidence: Reactome:R-HSA-448632 IL34 forms a noncovalently linked dimer (Ma et al. 2012) whereas CSF1 contains an intersubunit disulfide bond. The structure of the IL34:CSF1R complex shows a similar ligand-receptor assembly to that of CSF1:CSF1R. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6787820 | ACCEPT | Summary: Reactome pathway assertion for extracellular IL34 stimulation of CSF1R in myeloid cells. Reason: Consistent with experimental evidence that IL34 engages CSF1R from the extracellular region. Supporting Evidence: Reactome:R-HSA-6787820 Like CSF1, IL34 stimulation of CSF1R leads to phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2 in human monocytes (Lin et al. 2008). |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8981657 | ACCEPT | Summary: Reactome reaction assertion for extracellular IL34 dimer binding to PTPRZ1. Reason: Consistent with experimental evidence that IL34 acts in the extracellular region to bind cell-surface receptors. Supporting Evidence: Reactome:R-HSA-8981657 Interleukin-34 (IL34) signals via the Colony-stimulating factor-1 receptor (CSF1R). It can also bind Receptor-type protein-tyrosine phosphatase zeta (PTPRZ1), a cell surface chondroitin sulfate (CS) proteoglycan. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9009485 | ACCEPT | Summary: Reactome reaction assertion for extracellular IL34:CSF1 heteromer binding to CSF1R. Reason: Consistent with experimental evidence that IL34 acts in the extracellular region to engage CSF1R. Supporting Evidence: Reactome:R-HSA-9009485 Interleukin-34 (IL34) can bind Macrophage colony-stimulating factor 1 (CSF1). The IL34:CSF1 heteromer may bind Macrophage colony-stimulating factor 1 receptor (CSF1R) facilitating receptor maturation and cellular trafficking. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9009488 | ACCEPT | Summary: Reactome reaction assertion for extracellular IL34 binding to CSF1. Reason: Consistent with experimental evidence that extracellular IL34 functions in the extracellular region. Supporting Evidence: Reactome:R-HSA-9009488 Interleukin-34 (IL34) can bind Macrophage colony-stimulating factor 1 (CSF1) to form a heteromer, which subsequently binds CSF1R (Segaliny et al. 2015). |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9009554 | ACCEPT | Summary: Reactome reaction assertion for extracellular IL34 dimer:SDC1 binding to CSF1R. Reason: Consistent with experimental evidence that IL34 acts in the extracellular region. Supporting Evidence: Reactome:R-HSA-9009554 Interleukin-34 (IL34) can bind Syndecan-1 (SDC1), a cell surface proteoglycan. Low levels of SDC1 may sequester IL34 at the cell surface and prevent it from binding Macrophage colony-stimulating factor 1 receptor (CSF1R), while high SDC1 levels may facilitate IL34-CSF1R signaling (Segaliny et al. 2015). |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9009558 | ACCEPT | Summary: Reactome reaction assertion for extracellular IL34 dimer binding to SDC1. Reason: Consistent with experimental evidence that IL34 acts in the extracellular region. Supporting Evidence: Reactome:R-HSA-9009558 IL34 dimers can bind to the chondroitin sulphate of SDC1. Subsequently, SDC1 modulates IL34-induced CSF1R signaling pathways (Segaliny et al. 2015). |
| GO:0008284 positive regulation of cell population proliferation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference from PTN002823014 reflecting IL34's mitogenic/trophic effect on CSF1R-expressing myeloid cells. Reason: Retained as non-core: stimulation of target cell proliferation is a downstream cellular response to CSF1R activation, and the lineage-specific term GO:0120041 (positive regulation of macrophage proliferation) is captured in core_functions. Supporting Evidence: PMID:18467591 One of the highly selective proteins was a previously undescribed ligand, designated interleukin-34 (IL-34), which stimulates monocyte viability but does not affect responses in a wide spectrum of other assays. |
| GO:0008284 positive regulation of cell population proliferation | IDA PMID:18467591 Discovery of a cytokine and its receptor by functional scree... | KEEP AS NON CORE | Summary: Direct experimental evidence showing that recombinant human IL34 promotes monocyte survival/proliferation and macrophage progenitor colony growth. Reason: Consistent with the IBA and IEA rows for GO:0008284; retained as a non-core downstream cellular effect alongside the lineage-specific macrophage proliferation term (GO:0120041) in core_functions. Supporting Evidence: PMID:18467591 One of the highly selective proteins was a previously undescribed ligand, designated interleukin-34 (IL-34), which stimulates monocyte viability but does not affect responses in a wide spectrum of other assays. |
| GO:0008284 positive regulation of cell population proliferation | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO mapping from IPR020415 (Interleukin-34) for positive regulation of cell population proliferation. Reason: Maintains consistency with the IBA and IDA annotations for GO:0008284. |
| GO:0010628 positive regulation of gene expression | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Orthology transfer from mouse Il34 for positive regulation of gene expression. Over-annotation of downstream transcriptional effects of CSF1R signaling. Reason: IL34 is an extracellular cytokine ligand; transcriptional induction in target myeloid cells is an indirect downstream consequence mediated by CSF1R-activated transcription factors (such as STAT3 and AP-1) rather than a direct molecular role of IL34. |
| GO:0010720 positive regulation of cell development | IEA GO_REF:0000117 | TOO GENERAL | Summary: Broad ARBA-predicted developmental regulation term already entailed by specific monocyte and macrophage differentiation annotations on IL34. Reason: True of IL34's role in myeloid development, but uninformative because the specific terms GO:0045651 (positive regulation of macrophage differentiation) and GO:0045657 (positive regulation of monocyte differentiation) are already asserted on this gene with direct experimental evidence. |
| GO:0010759 positive regulation of macrophage chemotaxis | IDA PMID:26754294 miR-28-5p-IL-34-macrophage feedback loop modulates hepatocel... | KEEP AS NON CORE | Summary: Tumor-derived IL34 mediates tumor-associated macrophage infiltration and chemotaxis in hepatocellular carcinoma. Reason: Note that PMID:26754294 is abstract-only in the local cache (full_text_available: false); the abstract establishes that miR-28-5p deficiency promotes HCC growth and metastasis via IL34-mediated tumor-associated macrophage (TAM) infiltration. Deferring to the GOA curator's reading of the full text for the experimental chemotaxis assay (`acts_upstream_of`), this annotation is retained as a non-core downstream cellular response to IL34/CSF1R signaling. Supporting Evidence: PMID:26754294 Through gene expression profiles and bioinformatics analysis, we identified interleukin-34 (IL-34) as a direct target of miR-28-5p, and the effects of miR-28-5p deficiency on HCC growth and metastasis was dependent on IL-34-mediated tumor-associated macrophage (TAM) infiltration. |
| GO:0030224 monocyte differentiation | NAS PMID:30066957 Interleukin-34, a comprehensive review. | MODIFY | Summary: Author statement from review article PMID:30066957 describing IL34's role in promoting monocyte differentiation. Replace with the regulatory term GO:0045657 (positive regulation of monocyte differentiation). Reason: As an extrinsic secreted cytokine, IL34 does not execute intrinsic cell-autonomous monocyte differentiation steps; rather, it positively regulates monocyte differentiation via CSF1R signaling. Replacing GO:0030224 with GO:0045657 (positive regulation of monocyte differentiation, already asserted on IL34 with IDA evidence from PMID:23409120) accurately reflects its regulatory role. Proposed replacements: positive regulation of monocyte differentiation Supporting Evidence: PMID:30066957 IL-34 is synthesized as a secreted homodimeric glycoprotein that binds to the extracellular domains of CSF-1R and receptor-type protein-tyrosine phosphatase-zeta (PTP-ΞΆ) in addition to the chondroitin sulfate chains of syndecan-1. These interactions result in activating several signaling pathways that regulate major cellular functions, including proliferation, differentiation, survival, metabolism, and cytokine/chemokine expression in addition to cellular adhesion and migration. |
| GO:0038145 macrophage colony-stimulating factor signaling pathway | NAS PMID:30066957 Interleukin-34, a comprehensive review. | MODIFY | Summary: Author statement from review article PMID:30066957 conflating CSF1R activation by IL34 with the CSF1/M-CSF-initiated signaling pathway term GO:0038145. Replace with the ligand-specific sibling term GO:0061514 (interleukin-34-mediated signaling pathway). Reason: In GO, GO:0038145 (macrophage colony-stimulating factor signaling pathway, defined as the series of molecular signals initiated by macrophage colony-stimulating factor / M-CSF binding to its receptor) and GO:0061514 (interleukin-34-mediated signaling pathway, defined as the series of molecular signals initiated by interleukin-34 binding to its receptor) are sibling terms under GO:0019221 (cytokine-mediated signaling pathway), not parent and child. Although IL34 and CSF1 share the receptor CSF1R, IL34 is a distinct cytokine (and also engages PTPRZ1 and SDC1), so the ligand-specific pathway term GO:0061514 (already annotated to IL34) is the more precise pathway term. Proposed replacements: interleukin-34-mediated signaling pathway Supporting Evidence: PMID:30066957 IL-34 is a novel cytokine that was identified in 2008 in a comprehensive proteomic analysis as a tissue-specific ligand of CSF-1 receptor (CSF-1R). PMID:22483114 Here, the crystal structure of dimeric IL-34 reveals a helical cytokine fold homologous to CSF-1, and we further show that the complex architecture of IL-34 bound to the N-terminal immunoglobulin domains of CSF-1R is similar to the CSF-1/CSF-1R assembly. |
| GO:0043235 signaling receptor complex | IPI PMID:22483114 Structural basis for the dual recognition of helical cytokin... | KEEP AS NON CORE | Summary: Crystal structure of the ternary complex of homodimeric human IL34 bound to two CSF1R ectodomains (D1-D3) demonstrates that IL34 is an integral component of the active ligand-bound CSF1R signaling receptor complex. Reason: Directly supported by X-ray crystallography in PMID:22483114. Retained as non-core because IL34 is a secreted extracellular ligand (GO:0005576) that transiently becomes part of the cell-surface receptor complex upon binding CSF1R. Supporting Evidence: PMID:22483114 Here, the crystal structure of dimeric IL-34 reveals a helical cytokine fold homologous to CSF-1, and we further show that the complex architecture of IL-34 bound to the N-terminal immunoglobulin domains of CSF-1R is similar to the CSF-1/CSF-1R assembly. |
| GO:0043410 positive regulation of MAPK cascade | IDA PMID:26754294 miR-28-5p-IL-34-macrophage feedback loop modulates hepatocel... | ACCEPT | Summary: IL34 engagement of CSF1R rapidly activates the intracellular ERK1/2 (MAPK1/MAPK3) cascade in monocytes and macrophages. Reason: PMID:26754294 is abstract-only in the local cache (full_text_available: false), so we defer to the GOA curator's reading of the full text for the experimental MAPK assay in macrophages, which is independently corroborated by Reactome:R-HSA-6787820 summarizing Lin et al. (2008) (PMID:18467591) that IL34 stimulation of CSF1R leads to ERK1/2 phosphorylation in human monocytes. Note that the qualifier is acts_upstream_of_or_within, which appropriately captures an extracellular ligand initiating an intracellular kinase cascade. Supporting Evidence: PMID:26754294 Through gene expression profiles and bioinformatics analysis, we identified interleukin-34 (IL-34) as a direct target of miR-28-5p, and the effects of miR-28-5p deficiency on HCC growth and metastasis was dependent on IL-34-mediated tumor-associated macrophage (TAM) infiltration. Reactome:R-HSA-6787820 Like CSF1, IL34 stimulation of CSF1R leads to phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2 in human monocytes (Lin et al. 2008). |
| GO:0045651 positive regulation of macrophage differentiation | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference from PTN002823014 reflecting IL34's conserved core role in promoting macrophage differentiation via CSF1R. Reason: Core biological function of IL34 across vertebrates, directly grounded by human experimental evidence (PMID:18467591, PMID:23409120). Supporting Evidence: PMID:23409120 We report here that IL-34 induces the differentiation of monocytes into CD14(high) CD163(high) CD1a(-) MΟ (IL-34-MΟ). Upon LPS stimulation, IL-34-MΟ exhibit an IL-10(high) IL-12(low) M2 profile and express low levels of the costimulatory molecules CD80 and CD86. |
| GO:0045651 positive regulation of macrophage differentiation | IDA PMID:23409120 IL-34 induces the differentiation of human monocytes into im... | ACCEPT | Summary: Direct experimental evidence showing that human IL34 induces the differentiation of primary human monocytes into immunosuppressive M2-like macrophages via CSF1R. Reason: Defining core biological process regulated by IL34/CSF1R signaling. Supporting Evidence: PMID:23409120 We report here that IL-34 induces the differentiation of monocytes into CD14(high) CD163(high) CD1a(-) MΟ (IL-34-MΟ). Upon LPS stimulation, IL-34-MΟ exhibit an IL-10(high) IL-12(low) M2 profile and express low levels of the costimulatory molecules CD80 and CD86. |
| GO:0045657 positive regulation of monocyte differentiation | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference from PTN002823014 reflecting IL34's conserved role in promoting monocyte differentiation. Reason: Directly grounded by experimental evidence in human monocytes (PMID:18467591, PMID:23409120). Supporting Evidence: PMID:23409120 We report here that IL-34 induces the differentiation of monocytes into CD14(high) CD163(high) CD1a(-) MΟ (IL-34-MΟ). Upon LPS stimulation, IL-34-MΟ exhibit an IL-10(high) IL-12(low) M2 profile and express low levels of the costimulatory molecules CD80 and CD86. |
| GO:0045657 positive regulation of monocyte differentiation | IDA PMID:23409120 IL-34 induces the differentiation of human monocytes into im... | ACCEPT | Summary: Direct experimental evidence showing that recombinant human IL34 promotes monocyte differentiation into macrophages. Reason: Core biological process controlled by IL34 via CSF1R. Supporting Evidence: PMID:23409120 We report here that IL-34 induces the differentiation of monocytes into CD14(high) CD163(high) CD1a(-) MΟ (IL-34-MΟ). Upon LPS stimulation, IL-34-MΟ exhibit an IL-10(high) IL-12(low) M2 profile and express low levels of the costimulatory molecules CD80 and CD86. |
| GO:0048714 positive regulation of oligodendrocyte differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Automated Ensembl Compara orthology transfer from mouse Il34 (Q8R1R4) for positive regulation of oligodendrocyte differentiation. Reason: Consistent with the manual ISS annotation from mouse Il34; retained as a non-core specialized central nervous system role peripheral to IL34's primary myeloid/microglial CSF1R signaling axis. |
| GO:0048714 positive regulation of oligodendrocyte differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Manual orthology transfer from mouse Il34 (Q8R1R4) for positive regulation of oligodendrocyte differentiation. Reason: Consistent with the IEA annotation for GO:0048714; retained as non-core. |
| GO:0051240 positive regulation of multicellular organismal process | IEA GO_REF:0000117 | TOO GENERAL | Summary: High-level ARBA-predicted grouping term already entailed by IL34's specific myeloid differentiation and signaling annotations. Reason: True of IL34's physiological functions, but uninformative because specific descendant processes (GO:0045651 positive regulation of macrophage differentiation, GO:0045657 positive regulation of monocyte differentiation) are already asserted on this gene. |
| GO:0061514 interleukin-34-mediated signaling pathway | IDA PMID:26754294 miR-28-5p-IL-34-macrophage feedback loop modulates hepatocel... | ACCEPT | Summary: IL34 directly initiates the interleukin-34-mediated signaling pathway by binding and dimerizing CSF1R on target myeloid cells. Reason: Canonical signaling pathway directly initiated by IL34 engagement of CSF1R (PMID:18467591, PMID:22483114, Reactome:R-HSA-6787820). Note that PMID:26754294 is abstract-only in the local cache (full_text_available: false), so we defer to the GOA curator's reading of its full text alongside the functional and structural evidence in PMID:18467591 and PMID:22483114. Supporting Evidence: PMID:26754294 Through gene expression profiles and bioinformatics analysis, we identified interleukin-34 (IL-34) as a direct target of miR-28-5p, and the effects of miR-28-5p deficiency on HCC growth and metastasis was dependent on IL-34-mediated tumor-associated macrophage (TAM) infiltration. PMID:18467591 In a separate functional screen, we used a collection of extracellular domains of transmembrane proteins to discover the receptor for IL-34, which was a known cytokine receptor, colony-stimulating factor 1 (also called macrophage colony-stimulating factor) receptor. |
| GO:0061518 microglial cell proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology transfer from mouse Il34 (Q8R1R4) reflecting the essential role of neuron-derived IL34 in promoting microglial proliferation in the central nervous system via CSF1R. Reason: Supporting microglial homeostasis and proliferation via CSF1R in the brain is a key non-redundant physiological function of IL34 in mammals (PMID:30066957). However, as an extrinsic secreted cytokine, IL34 positively regulates microglial cell proliferation via CSF1R rather than executing the cell-autonomous division process itself (compare GO:0030224 monocyte differentiation, which is modified to GO:0045657 positive regulation of monocyte differentiation). Because GO currently lacks a specific positive regulation of microglial cell proliferation term and replacing GO:0061518 with GO:0120041 (positive regulation of macrophage proliferation) would lose microglial cell-type specificity, GO:0061518 is retained as non-core and a new term (positive regulation of microglial cell proliferation) is proposed in proposed_new_terms. Supporting Evidence: PMID:30066957 In the steady state, IL-34 contributes to the development and maintenance of specific myeloid cell subsets in a tissue-specific manner: Langerhans cells in the skin and microglia in the brain. |
| GO:0120041 positive regulation of macrophage proliferation | IDA PMID:26754294 miR-28-5p-IL-34-macrophage feedback loop modulates hepatocel... | ACCEPT | Summary: Direct experimental evidence demonstrating that IL34 promotes macrophage proliferation (`acts_upstream_of`). Reason: Core trophic function of IL34 on CSF1R-expressing macrophages. Note that PMID:26754294 is abstract-only in the local cache (full_text_available: false), so we defer to the GOA curator's reading of the full text for the macrophage proliferation assay, which is corroborated by PMID:30066957 and Reactome:R-HSA-9009558. Supporting Evidence: PMID:26754294 Through gene expression profiles and bioinformatics analysis, we identified interleukin-34 (IL-34) as a direct target of miR-28-5p, and the effects of miR-28-5p deficiency on HCC growth and metastasis was dependent on IL-34-mediated tumor-associated macrophage (TAM) infiltration. PMID:30066957 These interactions result in activating several signaling pathways that regulate major cellular functions, including proliferation, differentiation, survival, metabolism, and cytokine/chemokine expression in addition to cellular adhesion and migration. Reactome:R-HSA-9009558 Interleukin-34 (IL34) is involved in the survival, proliferation and differentiation of monocytes and macrophages. |
| GO:2000026 regulation of multicellular organismal development | IEA GO_REF:0000117 | TOO GENERAL | Summary: High-level ARBA-predicted developmental regulation term already entailed by IL34's specific myeloid differentiation annotations. Reason: True of IL34's role in myeloid and microglial development, but uninformative because specific descendant terms (GO:0045651, GO:0045657) are already asserted on this gene. |
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Download this section (compressed HTML)Q: How do co-receptors syndecan-1 (SDC1) and receptor-type protein-tyrosine phosphatase zeta (PTPRZ1) quantitatively partition IL34 signaling between CSF1R-dependent myeloid/microglial trophic responses and CSF1R-independent signaling in neural and tumor tissues?
Experiment: Single-molecule TIRF imaging and quantitative phosphoproteomics of primary human monocytes and induced pluripotent stem cell-derived microglia stimulated with equimolar homodimeric IL34, homodimeric CSF1, or heterodimeric IL34:CSF1 in the presence and absence of SDC1 chondroitin sulfate chains to compare CSF1R dimer lifetime, internalization kinetics, and STAT3 and ERK1/2 phosphorylation dynamics.
Hypothesis: SDC1 binding concentrates IL34 at the plasma membrane and prolongs CSF1R surface residency compared with CSF1, producing distinct temporal profiles of ERK1/2 and STAT3 activation.
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