id: Q9W735
gene_symbol: prom1a
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:7955
  label: Danio rerio
description: prom1a (prominin 1a) is one of two zebrafish co-orthologs of vertebrate PROM1 (prominin-1, CD133),
  retained from the teleost-specific genome duplication; its paralog is prom1b. It encodes a pentaspan membrane
  glycoprotein with two large glycosylated extracellular loops. Prominins sit in cholesterol-rich plasma-membrane
  protrusions such as microvilli and primary cilia and in extracellular vesicles derived from them; mammalian PROM1
  is also required for photoreceptor outer-segment disc morphogenesis. prom1a is the more broadly expressed copy.
  It is maternally supplied, is expressed in embryonic proliferative zones of the central nervous system and sensory
  organs, in the lens and otic vesicle, in adult brain germinative zones of the forebrain and dorsal midbrain, on the
  vitreal side of the retinal inner nuclear layer and at low level in rods and cones, and in several adult organs
  including gill, intestine, kidney and gonads. A prom1a knockout was reported to leave photoreceptors intact, in
  contrast to prom1b mutants, so its specific functions remain unknown.
existing_annotations:
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  supporting_entities:
  - UniProtKB-SubCell:SL-0095
  review:
    summary: Endoplasmic reticulum, mapped from a UniProt by-similarity subcellular location.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prominins are plasma-membrane proteins of protrusions and extracellular vesicles; the ER is a biosynthetic
      transit compartment for any glycosylated membrane protein. No zebrafish data place Prom1a in the ER, and the
      term does not describe where the protein acts.
    supported_by:
    - &protrusion
      reference_id: PMID:32201384
      supporting_text: They are associated with plasma membrane protrusions, such as primary cilia, as well as extracellular
        vesicles derived thereof.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  supporting_entities:
  - UniProtKB:O43490
  review:
    summary: Endoplasmic reticulum, transferred from human PROM1 by sequence similarity.
    action: MARK_AS_OVER_ANNOTATED
    reason: Transit compartment; the functional locations of prominins are the apical plasma membrane, its protrusions
      and derived vesicles.
    supported_by:
    - *protrusion
- term:
    id: GO:0005793
    label: endoplasmic reticulum-Golgi intermediate compartment
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  supporting_entities:
  - UniProtKB-SubCell:SL-0098
  review:
    summary: ER-Golgi intermediate compartment, mapped from a UniProt by-similarity subcellular location.
    action: MARK_AS_OVER_ANNOTATED
    reason: Secretory transit compartment; not where Prom1a is thought to act, and not observed in zebrafish.
    supported_by:
    - *protrusion
- term:
    id: GO:0005793
    label: endoplasmic reticulum-Golgi intermediate compartment
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  supporting_entities:
  - UniProtKB:O43490
  review:
    summary: ER-Golgi intermediate compartment, transferred from human PROM1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Secretory transit compartment, as for the ER rows.
    supported_by:
    - *protrusion
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  supporting_entities:
  - UniProtKB:O43490
  review:
    summary: Plasma membrane, transferred from human PROM1.
    action: ACCEPT
    reason: Correct for a prominin; Prom1a keeps the five transmembrane segments and the extracellular loops of the
      family (bioinformatics RESULTS.md), and the paralog's GFP fusion localizes to the apical plasma membrane.
    supported_by:
    - &bioinf
      reference_id: file:DANRE/prom1a/prom1a-bioinformatics/RESULTS.md
      supporting_text: All five transmembrane segments of human PROM1 align without gaps in both copies
    - *protrusion
- term:
    id: GO:0005902
    label: microvillus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  supporting_entities:
  - MGI:MGI:1100886
  - PANTHER:PTN000506588
  - RGD:621435
  review:
    summary: Microvillus, from the PANTHER prominin node (mouse and rat Prom1).
    action: ACCEPT
    reason: Microvilli are a defining location of prominins across animals; no zebrafish-specific evidence argues
      against it for the broadly expressed epithelial copy.
    supported_by:
    - reference_id: PMID:21407811
      supporting_text: microvillus, cilium, filopodium) [3], [18], [20], [29] might be the underlying reason of such
        phenomenon as demonstrated in mature photoreceptors.
- term:
    id: GO:0005929
    label: cilium
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  supporting_entities:
  - MGI:MGI:1100886
  - PANTHER:PTN001100171
  - RGD:621435
  - UniProtKB:O43490
  review:
    summary: Cilium, from the PANTHER prominin node.
    action: ACCEPT
    reason: Prominins localize to primary cilia and regulate ciliary length in human cells and zebrafish (prom3);
      the location is ancestral to the family.
    supported_by:
    - *protrusion
    - reference_id: PMID:32201384
      supporting_text: These distinct loss-of-function approaches in two biological systems reveal that prom proteins
        are critical for the integrity and function of cilia.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  supporting_entities:
  - InterPro:IPR008795
  review:
    summary: Membrane, from the prominin InterPro signature.
    action: ACCEPT
    reason: Correct; multi-pass membrane protein.
    supported_by:
    - *bioinf
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  supporting_entities:
  - FB:FBgn0026189
  - MGI:MGI:1100886
  - PANTHER:PTN001100171
  review:
    summary: Apical plasma membrane, from the PANTHER prominin node (fly and mouse donors).
    action: ACCEPT
    reason: Apical enrichment is a conserved prominin property; the zebrafish paralog Prom1b-GFP is apical in retinal
      neuroepithelia.
    supported_by:
    - &apical
      reference_id: PMID:22492354
      supporting_text: We also generated a transgenic line in which GFP is fused with Prominin1b (Prom1b-GFP), a cholesterol-interacting
        pentaspan membrane protein that is enriched at the apical region of polarized cells, including retinal neuroepithelia
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  supporting_entities:
  - UniProtKB-SubCell:SL-0015
  review:
    summary: Apical plasma membrane, from UniProt subcellular location.
    action: ACCEPT
    reason: As for the IBA row.
    supported_by:
    - *apical
- term:
    id: GO:0031528
    label: microvillus membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  supporting_entities:
  - UniProtKB-SubCell:SL-0294
  review:
    summary: Microvillus membrane, from UniProt subcellular location.
    action: ACCEPT
    reason: Consistent with the family's location in microvilli.
    supported_by:
    - *protrusion
- term:
    id: GO:0032528
    label: microvillus organization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  supporting_entities:
  - FB:FBgn0026189
  - PANTHER:PTN000506588
  review:
    summary: Microvillus organization, from the PANTHER prominin node (Drosophila prominin-like donor).
    action: KEEP_AS_NON_CORE
    reason: Plausible for a prominin that shapes membrane protrusions, but no zebrafish data address it and the
      copy's knockout phenotype is not described beyond the retina.
    supported_by:
    - *protrusion
- term:
    id: GO:0060219
    label: camera-type eye photoreceptor cell differentiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  supporting_entities:
  - MGI:MGI:1100886
  - PANTHER:PTN002733197
  - UniProtKB:O43490
  review:
    summary: Camera-type eye photoreceptor cell differentiation, from the PANTHER PROM1 node (mouse Prom1 and human
      PROM1).
    action: MARK_AS_OVER_ANNOTATED
    reason: The photoreceptor role of the ancestral gene has gone to prom1b in zebrafish. prom1b loss disrupts
      outer-segment morphogenesis and causes cone degeneration, whereas the same study concluded that prom1a is not
      the copy that matters in photoreceptors. prom1a transcripts are present in rods and cones, but at about a third
      to a quarter of the prom1b level (scRNA-seq reanalysis). The row is marked rather than removed because a minor,
      masked contribution cannot be excluded without a double mutant.
    supported_by:
    - &lu
      reference_id: PMID:31362982
      supporting_text: The Prom1 orthologs in zebrafish include prom1a and prom1b, and our results showed that prom1b,
        rather than prom1a, plays an important role in zebrafish photoreceptors.
    - reference_id: file:DANRE/prom1a/prom1a-bioinformatics/RESULTS.md
      supporting_text: Both copies are detected in rods and in every cone type, with prom1b three to four times more
        abundant than prom1a
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - CONTEXT_OR_TISSUE_MISMATCH
      source_entities:
      - source_id: PANTHER:PTN002733197
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: The PROM1 node rightly carries the photoreceptor role of mammalian PROM1, but after the teleost duplication
          the photoreceptor requirement is carried by prom1b; a same-node IBA cannot see this split.
      - source_id: MGI:MGI:1100886
        source_label: Prom1 (mouse)
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: Mouse Prom1 is required for outer-segment disc morphogenesis; that role maps to prom1b in zebrafish.
- term:
    id: GO:0071914
    label: prominosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  supporting_entities:
  - MGI:MGI:1100886
  - MGI:MGI:2138997
  - PANTHER:PTN001100171
  - RGD:621435
  review:
    summary: Prominosome (prominin-containing extracellular vesicle), from the PANTHER prominin node.
    action: KEEP_AS_NON_CORE
    reason: Release of prominin-containing vesicles from protrusions is a family property shown in mammals; not examined
      in zebrafish.
    supported_by:
    - *protrusion
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence
    similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied
    by conservative changes to GO terms applied by UniProt
  findings: []
- id: PMID:20503380
  title: Expression of the zebrafish CD133/prominin1 genes in cellular proliferation zones in the embryonic central
    nervous system and sensory organs.
  findings: []
  full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract only. Embryonic whole-mount in situ of both copies; complementary and overlapping domains
      in proliferative zones.
- id: PMID:21407811
  title: Distinct and conserved prominin-1/CD133-positive retinal cell populations identified across species.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text. Adult retina in situ; both copies in the ONL, differential INL expression (prom1a vitreal,
      prom1b scleral).
- id: PMID:23723983
  title: Spatial distribution of prominin-1 (CD133)-positive cells within germinative zones of the vertebrate brain.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text. Adult brain; prom1a rostral (prosencephalon, dorsal mesencephalon), prom1b caudal (rhombencephalon),
      little overlap.
- id: PMID:22492354
  title: Loss of Llgl1 in retinal neuroepithelia reveals links between apical domain size, Notch activity and neurogenesis.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Full text. Prom1b-GFP used as an apical marker; cited here for the paralog.
- id: PMID:31362982
  title: Deletion of the transmembrane protein Prom1b in zebrafish disrupts outer-segment morphogenesis and causes photoreceptor
    degeneration.
  findings: []
  full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: DISPUTED
    review_notes: Abstract cached. The full text (read on PMC, not cached) reports TALEN alleles for both copies and
      no photoreceptor defect in prom1a mutants up to 11 months. Corbeil et al. (PMID:31704774) questioned the conclusion
      that prom1a has no photoreceptor role, citing prom1a splice variants and expression in the retina.
- id: PMID:31704774
  title: Deciphering the roles of prominins in the visual system.
  findings: []
  full_text_unavailable: true
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Letter; no abstract text cached. Challenges the prom1b-only interpretation.
- id: PMID:32201384
  title: 'Prominins control ciliary length throughout the animal kingdom: New lessons from human prominin-1 and zebrafish
    prominin-3.'
  findings: []
  full_text_unavailable: true
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract only. Family-level; prominins at protrusions and cilia; zebrafish prom3 knockdown affects
      Kupffer's vesicle cilia.
- id: PMID:34462505
  title: Partitioning of gene expression among zebrafish photoreceptor subtypes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Adult photoreceptor scRNA-seq (GSE175929); reanalysed for prom1a/prom1b in the bioinformatics folder.
- id: file:DANRE/prom1a/prom1a-bioinformatics/RESULTS.md
  title: prom1a / prom1b sequence, synteny and expression analysis
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Manual audit verified the sidecar supports both PROM1 duplicates retaining full prominin topology,
      duplicated-block synteny and photoreceptor expression, with prom1a broader and prom1b retinally enriched.
  findings: []
core_functions:
- description: Pentaspan prominin glycoprotein of the apical plasma membrane and its protrusions (microvilli, primary
    cilia), the broadly expressed zebrafish PROM1 co-ortholog (maternal, forebrain and dorsal midbrain germinative
    zones, retinal inner nuclear layer, epithelial organs). Its molecular function is not established.
  locations:
  - id: GO:0016324
    label: apical plasma membrane
  - id: GO:0005929
    label: cilium
  supported_by:
  - *protrusion
  - reference_id: PMID:23723983
    supporting_text: Note that major sites of expression of prominin-1a are mainly located in the prosencephalic (rostral)
      and dorsal mesencephalic (tectal) domain (A), whereas prominin-1b is predominantly found in the rhombencephalic
      brainstem (caudal) domain (B).
suggested_questions:
- question: Does prom1a contribute to outer-segment morphogenesis when prom1b is absent (prom1a; prom1b double mutants),
    and is prom1a upregulated in prom1b mutants?
- question: What does prom1a do in the maternal embryo and in adult epithelial organs (intestine, kidney, gill) where
    prom1b is not detected?
- question: Do Prom1a splice variants reach the photoreceptor outer segment?
suggested_experiments:
- hypothesis: The photoreceptor split between the copies is due to expression level, not protein function.
  description: Express Prom1a from the prom1b promoter (or a photoreceptor promoter) in prom1b mutants and score outer-segment
    morphology and cone survival.
  experiment_type: cross-rescue
- hypothesis: prom1a and prom1b are partly redundant in photoreceptors.
  description: Compare prom1b single and prom1a; prom1b double mutants for outer-segment defects and rod survival, and
    measure prom1a mRNA in prom1b mutants.
  experiment_type: double mutant