kitlga encodes Kit ligand a, a zebrafish co-ortholog of mammalian KITLG (stem cell factor, SCF; also called mast cell growth factor and c-Kit ligand). It is a four-helix cytokine-like SCF-family growth factor synthesized as a single-pass type I membrane protein that can also be released as a soluble extracellular ligand, acting through juxtacrine and paracrine signaling. Its defining molecular function is to bind and activate the Kita receptor tyrosine kinase (the zebrafish KIT-a ortholog), triggering the conserved KIT-RAS/MAPK and PI3K/AKT signaling cascades in receiving cells. kitlga arose together with its paralog kitlgb from the teleost whole-genome duplication of the ancestral kit ligand, with the two paralogs partitioning ancestral roles and their receptors (kita, kitb); kitlga is the paralog that retains the ancestral pigment-cell role and kitlgb does not substitute for it. Through Kita engagement, kitlga controls embryonic melanocyte migration, survival, number and pattern, establishes and maintains adult melanophore progenitors, and contributes to proliferation of KIT-expressing progenitors including cooperation with erythropoietin in erythroid expansion. It is produced by supporting/niche cells such as trunk somitic mesoderm and skin, and acts on neighboring Kita-expressing target cells.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005173 stem cell factor receptor binding | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO annotation (SCF domain IPR003452) assigning stem cell factor receptor binding. kitlga is the functional ligand for the Kita receptor tyrosine kinase, as demonstrated by morpholino phenocopy of the kita-null allele, genetic interaction with a sensitized kita allele, and kita-dependent hyperpigmentation on overexpression. Under GO ligand curation conventions, receptor-specific binding on a ligand is replaced by the effector ligand activity term (GO:0005125 cytokine activity). Reason: GO:0005173 (stem cell factor receptor binding) is a receptor-specific binding term under GO:0005126 (cytokine receptor binding) rather than GO:0048018 (receptor ligand activity). Replace with GO:0005125 (cytokine activity) to capture kitlga's agonistic cytokine ligand role. Proposed replacements: cytokine activity Supporting Evidence: PMID:17257055 we conclude that kitla is the functional kita ligand in zebrafish embryonic melanocyte development and that kitla promotes all of the kita-dependent functions in embryonic melanocyte development PMID:17257055 overexpression of kitla results in a hyperpigmented embryo with an increase in the number and size of melanocytes |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic subcellular-location annotation. kitlga is synthesized as a membrane-associated ligand that can be released as a soluble, biologically active extracellular form (UniProt "Secreted"), so the extracellular region is a genuine functional location for the soluble ligand. Reason: Consistent with the secreted soluble SCF-family ligand form; correct functional location for paracrine signaling. |
| GO:0005856 cytoskeleton | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic annotation derived from the "Cytoplasm, cytoskeleton" UniProt subcellular-location keyword, which is an ARBA by-similarity assignment. kitlga is a secreted/membrane cytokine ligand; a cytoskeletal association is not a functional site of action and rests only on a by-similarity keyword. Reason: Weakly supported (by-similarity keyword only) and not a functional location for a cytokine ligand; retain as non-core rather than a core location. Mirrors the human KITLG review of the same by-similarity keyword. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBD/IBA) annotation placing the kit ligand family as active at the plasma membrane at ancestral node PTN002611905. Membrane-anchored SCF/Kit ligand signals to the Kit receptor from the plasma membrane (juxtacrine), and kitlga is a single-pass type I membrane protein, so is_active_in plasma membrane is appropriate. Reason: Sound node placement; membrane-bound kit ligand is functionally active at the plasma membrane. Core functional location for the membrane-bound form. The node is seeded by well-characterized mammalian members (mouse Kitl, human KITLG) and is consistent with the conserved single-pass topology. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic subcellular-location annotation consistent with the single-pass type I plasma-membrane topology of kitlga (UniProt "Cell membrane; Single-pass type I membrane protein"). Reason: Correct; redundant with the IBA is_active_in plasma-membrane annotation for the membrane-anchored ligand. |
| GO:0007155 cell adhesion | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO mapping from the SCF domain (IPR003452). Membrane-bound kit ligand can promote adhesion/retention of Kit-expressing cells at cell-cell contacts, so the term is not unreasonable, but the mapping is broad and cell adhesion is a secondary consequence of juxtacrine ligand presentation rather than a core function of kitlga. Reason: Plausible for the membrane form but derived from a broad domain-to-GO mapping and peripheral to the core receptor-binding function; retain as non-core. Mirrors the human KITLG review of the same InterPro2GO term. |
| GO:0008284 positive regulation of cell population proliferation | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic annotation (node PTN002611905) that kit ligand positively regulates cell proliferation. SCF/Kit ligand is a mitogenic growth factor for Kit-expressing cells; in zebrafish, kitlga overexpression increases melanocyte number (kita-dependent hyperpigmentation), and the ligand cooperates with erythropoietin to expand erythroid progenitors, consistent with this term. Reason: Core process: kitlga drives proliferation/expansion of Kita-expressing target cells. Node placement is sound and consistent with both the family and zebrafish-specific gain-of-function data. Supporting Evidence: PMID:17257055 overexpression of kitla results in a hyperpigmented embryo with an increase in the number and size of melanocytes |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: General membrane location from InterPro. kitlga is a single-pass type I membrane protein, so this is correct but less informative than the plasma membrane annotations. Reason: Correct but a general parent term; the specific plasma membrane annotations are the informative ones. Acceptable as a broad IEA location. |
| GO:0030027 lamellipodium | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic subcellular-location annotation from an ARBA by-similarity keyword. In human KITLG, transmembrane ligand was directly observed in lamellipodia by immunofluorescence (PMID:26522471), but for zebrafish kitlga this is only a by-similarity keyword transfer with no direct zebrafish evidence. Reason: Cell-projection localization derived from a by-similarity keyword; plausible for the membrane form but non-core and not experimentally established in zebrafish. |
| GO:0030175 filopodium | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic subcellular-location annotation from an ARBA by-similarity keyword. As with lamellipodium, the transmembrane ligand was directly localized to filopodia for human KITLG (PMID:26522471), but for zebrafish kitlga this rests only on a by-similarity keyword. Reason: Cell-projection localization from a by-similarity keyword; plausible but non-core and not experimentally established in zebrafish. |
| GO:0030318 melanocyte differentiation | IDA PMID:17257055 Gene Duplication of the zebrafish kit ligand and partitionin... | KEEP AS NON CORE | Summary: Direct assay (expression + gain-of-function) placing kitlga upstream of/within melanocyte differentiation. kitla mRNA is expressed along the medial melanocyte migration route and later in skin, and kitla overexpression produces kita-dependent hyperpigmentation with increased melanocyte number and size. kitlga is the pigment-role paralog; kitlgb does not substitute. This is a well-supported developmental/lineage outcome downstream of the core Kita-ligand activity. Reason: Strongly supported zebrafish-specific in vivo phenotype, but it is a developmental/lineage process (the gene acts upstream of it as the ligand) rather than the core molecular function; retain as non-core. Supporting Evidence: PMID:17257055 kitla mRNA is expressed in the trunk adjacent to the notochord in the middle of each somite during stages of melanocyte migration and later expressed in the skin, when the receptor is required for melanocyte survival PMID:17257055 overexpression of kitla results in a hyperpigmented embryo with an increase in the number and size of melanocytes |
| GO:0030318 melanocyte differentiation | IGI PMID:17257055 Gene Duplication of the zebrafish kit ligand and partitionin... | KEEP AS NON CORE | Summary: Genetic-interaction evidence: a low dose of kitla morpholino synergistically enhances the sensitized temperature-sensitive kita allele (kitajle99), placing kitlga in the kita genetic pathway for melanocyte development. Only kitla, not kitlb, shows this interaction, confirming kitlga as the functional Kita ligand. Reason: Confirms kitlga acts within the kita melanocyte-development pathway, but the process is a developmental/lineage outcome downstream of the ligand activity; retain as non-core. Supporting Evidence: PMID:17257055 kitla morpholino, but not kitlb morpholino, interacts genetically with a sensitized allele of kita, confirming that kitla is the functional ligand to kita |
| GO:0030318 melanocyte differentiation | IMP PMID:17257055 Gene Duplication of the zebrafish kit ligand and partitionin... | KEEP AS NON CORE | Summary: Loss-of-function (morpholino) evidence: kitla morphants, but not kitlb morphants, phenocopy the kita-null allele, with defects in both melanocyte migration and survival. This establishes kitlga as required for kita-dependent melanocyte development. Reason: Well-supported requirement, but a developmental/lineage process (acts upstream of it as the ligand) rather than the core molecular function; retain as non-core. Supporting Evidence: PMID:17257055 kitla morphants, but not kitlb morphants, phenocopy the null allele of kita, with defects for both melanocyte migration and survival |
| GO:0030318 melanocyte differentiation | IMP PMID:23364329 On the embryonic origin of adult melanophores: the role of E... | KEEP AS NON CORE | Summary: Mutant (loss-of-function) evidence from an independent study: the sparse like (slk) mutant, identified as kit ligand a (kitlga), lacks larval and metamorphic melanophores, indicating kitlga is required for establishment/survival of embryonic melanophore progenitors. This corroborates the melanocyte-lineage role with a genetic lesion (not morpholino). Reason: Independent experimental support for the melanocyte-lineage role, but a developmental/lineage process downstream of the core ligand activity; retain as non-core. Supporting Evidence: PMID:23364329 We show that the sparse like (slk) mutant lacks larval and metamorphic melanophores and identify kit ligand a (kitlga) as the underlying gene. Our data suggest that kitlga is required for the establishment or survival of embryonic MPs |
| GO:0030318 melanocyte differentiation | IMP PMID:9007256 Zebrafish pigmentation mutations and the processes of neural... | KEEP AS NON CORE | Summary: Mutant-phenotype annotation to the same kitlga genotype (ZDB-GENO-120316-63) from the large-scale Tuebingen pigmentation mutagenesis screen, which isolated chromatophore mutants later mapped to genes including kit ligand a. The cached record is abstract-only and the abstract describes the screen broadly rather than naming kitlga, so the annotation rests on the ZFIN curator's genotype assignment (full text not accessible); the melanocyte-lineage role is independently well established. Reason: Consistent with the established melanocyte-lineage role; per curation policy an experimental annotation is not removed merely because the cached abstract does not name the gene. A developmental/lineage process downstream of the core ligand activity; retain as non-core. Supporting Evidence: PMID:9007256 these mutations include strong candidates for genes important in various aspects of chromatophore differentiation and survival |
| GO:0038109 Kit signaling pathway | IGI PMID:17257055 Gene Duplication of the zebrafish kit ligand and partitionin... | NEW | Summary: Proposed new annotation: kitlga is the functional extracellular ligand that activates the zebrafish Kita receptor tyrosine kinase to initiate the Kit signaling pathway, as shown by morpholino phenocopy of kita-null embryos, synergistic genetic interaction with a sensitized kita allele (kitajle99), and strictly kita-dependent hyperpigmentation upon kitla overexpression. Reason: Under GO signaling-pathway curation conventions, extracellular ligands that directly engage and activate the pathway receptor are annotated to the signaling pathway biological process term (GO:0038109 Kit signaling pathway). Supporting Evidence: PMID:17257055 kitla morpholino, but not kitlb morpholino, interacts genetically with a sensitized allele of kita, confirming that kitla is the functional ligand to kita PMID:17257055 We conclude that following genome duplication, kita and kitla have maintained their receptor-ligand relationship, coevolved complementary expression patterns, and that functional analysis reveals that most or all of the kita receptor's function in the embryo are promoted by its interaction with kitla. |
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