kitlga (Danio rerio) — curation notes

UniProt: Q56JH6 (Kit ligand a). ZFIN: ZDB-GENE-070424-1. Synonyms: kitla.
Taxon: NCBITaxon:7955. 272 aa, single-pass type I membrane protein, SCF family,
four-helix cytokine-like core (IPR009079), SCF domain (IPR003452 / PF02404).

1. Identity and teleost-duplication context

Zebrafish retained two co-orthologs of mammalian KITLG/Kitl (stem cell factor, SCF)
following the teleost whole-genome duplication: kitlga (this gene, historical alias
kitla, on chromosome 25) and kitlgb (kitlb, on chromosome 4). The receptors
duplicated in parallel (kita, kitb).

• Phylogeny places both zebrafish genes as co-orthologs of tetrapod Kitl, with the
  duplication occurring in the teleost lineage: PMID:17257055 and PMID:17257055.
• The paralogs diverged strongly in sequence (kitla ~29% identical / 43% similar to
  mouse Kitl) and in splice-form structure: kitla retained exon 6 (nine exons matching
  the nine murine exons), whereas kitlb lost the exon-6-homologous sequence
  PMID:17257055.
• Subfunctionalization / pigmentation-role partitioning: kitlga is the paralog that
  retains the ancestral melanocyte (pigment) role; kitlgb does NOT substitute for it.
  MO knockdown of kitla, but not kitlb, phenocopies the kita-null allele
  PMID:17257055, and only kitla interacts
  genetically with a sensitized kita allele PMID:17257055. kitlb is not required for embryonic
  melanocyte migration or survival PMID:17257055.
• The deep-research report adds (from non-cached primary literature) that the ligand
  systems are receptor-specialized (Kitlga→Kita, Kitlgb→Kitb) and that embryonic
  HSC-specification is instead assigned mainly to Kitlgb–Kitb, so mammalian-KITLG or
  kitlgb roles should not be transferred wholesale to Q56JH6 (deep-research falcon,
  hultman2007 / yao2013 / mahony2018).

2. Core molecular function — Kita ligand (SCF-family cytokine)

kitlga is a signaling cytokine ligand, not an enzyme/transporter/structural protein.
Its defining molecular function is to bind and activate the Kita receptor tyrosine
kinase (the zebrafish KIT-a ortholog), i.e. stem cell factor receptor binding /
cytokine/growth-factor activity.

• Functional-ligand conclusion: PMID:17257055.
• Growth-factor (mitogenic) activity in vivo: kitla overexpression causes
  kita-dependent hyperpigmentation through increased melanocyte number and size
  PMID:17257055 and this requires kita
  PMID:17257055.
• Domain/family support: UniProt assigns the SCF family and four-helix cytokine-like
  core (IPR009079, IPR003452/PF02404); RecName "Kit ligand", AltNames "Stem cell
  factor", "Mast cell growth factor", "c-Kit ligand" (kitlga-uniprot.txt).
• The signaling output is the conserved KIT–RAS/MAPK cascade (Reactome R-DRE entries for
  Signaling by SCF-KIT, RAF/MAP kinase cascade, PI3K/AKT; kitlga-uniprot.txt DR lines).

3. Localization

Synthesized as a membrane-associated (single-pass type I) ligand that can be released as
a soluble extracellular form; operative compartments are the producing-cell surface
(juxtacrine) and the extracellular/paracrine space.
- UniProt SUBCELLULAR LOCATION: Cell membrane; Secreted; also cytoskeleton and cell
projection (filopodium/lamellipodium) keywords, all ARBA by-similarity
(kitlga-uniprot.txt). The cytoskeleton and filopodium/lamellipodium calls are
by-similarity keyword transfers (the same by-similarity keywords underlie the human
KITLG annotations, where the projection localizations were directly observed for the
transmembrane form by IF, PMID:26522471); for zebrafish they are electronic and
non-core.

4. Biological processes (zebrafish-specific in vivo phenotypes)

• Melanocyte / pigment-pattern development (GO:0030318): the strongest and most
  specific experimental role. Expression along the medial melanocyte-migration route
  (18–30 hpf) then in skin (4–5 dpf) PMID:17257055. Loss of function (morpholino) and gain of function
  establish requirement for both migration and survival. A second, independent line:
  the sparse like (slk) mutant is kitlga, lacking larval and metamorphic melanophores
  PMID:23364329. The Kelsh 1996
  mutagenesis screen PMID:9007256 isolated the pigmentation mutant (the ZFIN genotype
  ZDB-GENO-120316-63 later mapped to kitlga) among chromatophore-number/differentiation
  genes; this abstract does not name kitlga (screen paper, abstract-only cache), so the
  annotation rests on the ZFIN curator's genotype assignment.
• Positive regulation of cell population proliferation (GO:0008284): SCF is a
  mitogen for KIT+ cells; in zebrafish, kitlga drives increased melanocyte number
  (hyperpigmentation) and, per deep research, cooperates with Epo to expand erythroid
  progenitors (Oltova 2020 preprint, not cached).
• Note on qualifiers: the GO:0030318 rows use acts_upstream_of_or_within, i.e. kitlga
  acts upstream of / within melanocyte differentiation (as the ligand), not that it is
  itself a melanocyte differentiating — consistent with treating it as a non-core
  developmental/lineage outcome relative to the core ligand activity.

5. Curation decisions summary

Core (ACCEPT): GO:0005173 stem cell factor receptor binding (IEA); GO:0005886 plasma
membrane (IBA is_active_in, and IEA); GO:0008284 positive regulation of cell population
proliferation (IBA); GO:0005576 extracellular region (IEA); GO:0016020 membrane (IEA,
general parent).

Non-core (KEEP_AS_NON_CORE): GO:0005856 cytoskeleton (by-similarity keyword);
GO:0007155 cell adhesion (InterPro2GO, broad/secondary); GO:0030027 lamellipodium and
GO:0030175 filopodium (by-similarity keyword, non-core projection localizations); all
five GO:0030318 melanocyte differentiation rows (well-supported developmental/lineage
phenotype, but downstream of the core ligand activity).

No annotations warranted REMOVE (no generic protein binding GO:0005515 row is present;
no contradicted or demonstrably wrong terms). No NEW existing_annotation added — the
core molecular function (stem cell factor receptor binding) is already present, and
cytokine/growth-factor activity is captured in core_functions rather than manufactured
as a new GOA-style row. Comparator/participation tests were not triggered because no new
process term is proposed.

Re-review 2026-09-29

• Resolved the two core_functions/existing_annotations consistency warnings.
• GO:0005125 cytokine activity (core function 2's molecular_function) was not in existing_annotations: added it as a NEW row (evidence_type ISS, action NEW). Justified by the participation test (kitlga IS the SCF-family cytokine ligand that activates Kita) and comparator check (human ortholog KITLG P21583 carries GO:0005125, QuickGO IEA). It is a distinct MF branch from the already-annotated GO:0005173 stem cell factor receptor binding (which sits under cytokine receptor binding), so not redundant [PMID:17257055 "kitla is the functional kita ligand in zebrafish"; "overexpression of kitla results in a hyperpigmented embryo with an increase in the number and size of melanocytes"].
• GO:0030318 melanocyte differentiation: it IS present in existing_annotations (rows 10-14, all KEEP_AS_NON_CORE) as a downstream developmental output in which kitlga acts as the signaling ligand rather than the differentiating cell. Removed it from core_functions[0].directly_involved_in for consistency (a non-core process should not be a directly_involved_in of a core function); the core proliferation process GO:0008284 remains.
• Existing reference_reviews on the 3 PMIDs retained. Validation: 0 errors.