id: Q09436
gene_symbol: mex-6
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: >-
  MEX-6 is a cytoplasmic CCCH-type tandem zinc finger (TZF) RNA-binding protein of the
  TTP/ZFP36 family that functions in the early Caenorhabditis elegans embryo to establish
  soma/germline asymmetry along the anterior-posterior axis. It is the close, nearly
  identical paralog of MEX-5 and acts largely redundantly with it: single loss of mex-6 is
  mostly silent, whereas removing both mex-5 and mex-6 disrupts embryonic viability and the
  asymmetric distribution of maternally supplied determinants (PLK-1, PIE-1, MEX-1, POS-1).
  Like MEX-5, MEX-6 is broadly cytoplasmic and becomes anterior-enriched in the one-cell
  zygote, acting downstream of cortical PAR polarity and the PAR-1 kinase during the
  establishment phase of polarization. MEX-6 contains two tandem C3H1-type zinc fingers that
  bind mRNA (including 3'-UTR sequences) and coordinate zinc. It is also a substrate and
  adaptor for the mitotic Polo-like kinases PLK-1 and PLK-2; MBK-2/DYRK2-primed
  phosphorylation of a threonine adjacent to the zinc fingers creates a docking site for the
  polo-box domains of PLK-1/PLK-2, and MEX-5/MEX-6 in turn are required for the anterior
  enrichment of these kinases.
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: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:10882103
  title: MEX-5 and MEX-6 function to establish soma/germline asymmetry in early C. elegans
    embryos.
  findings:
  - statement: mex-5 and mex-6 are two nearly identical genes that link PAR cortical asymmetry
      to downstream protein asymmetries.
    supporting_text: We provide evidence that two nearly identical genes, mex-5 and mex-6,
      link PAR asymmetry to those subsequent protein asymmetries.
  - statement: The paralogs act downstream of the PAR network to pattern expression of
      nonlocalized maternal mRNAs.
    supporting_text: This network is required for subsequent asymmetries in the expression
      patterns of several proteins that are encoded by nonlocalized, maternally expressed
      mRNAs.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Founding paper that identifies and names mex-6 (with mex-5); PubMed-verified.
      Abstract characterizes MEX-5 localization in detail but explicitly establishes the
      redundant mex-5/mex-6 pair as the link between PAR asymmetry and downstream germline
      protein asymmetries. Full text abstract-only in cache.
- id: PMID:12588843
  title: Polarization of the C. elegans zygote proceeds via distinct establishment and
    maintenance phases.
  findings:
  - statement: Zygote polarization along the A-P axis depends on cortical PAR and cytoplasmic
      MEX-5/6 proteins.
    supporting_text: Polarization of the C. elegans zygote along the anterior-posterior axis
      depends on cortically enriched (PAR) and cytoplasmic (MEX-5/6) proteins
  - statement: MEX-5 and MEX-6 (CCCH finger proteins) act with PAR-1 in the establishment
      phase in a feedback loop regulating the posterior domain.
    supporting_text: The kinase PAR-1 and the CCCH finger proteins MEX-5 and MEX-6 also
      function during the establishment phase in a feedback loop to regulate growth of
      the posterior domain.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Live imaging of GFP-tagged MEX-6 (with MEX-5, PAR-2/6, PIE-1); places
      MEX-6 in the establishment phase of zygote polarization. PubMed-verified; abstract-only
      in cache. Source of the mex-6 IDA cytoplasm and (full-text) P granule annotations.
- id: PMID:17264081
  title: Molecular basis of RNA recognition by the embryonic polarity determinant MEX-5.
  findings:
  - statement: MEX-5 (the near-identical paralog of MEX-6) binds RNA with high affinity but
      low sequence specificity, recognizing tracts of six or more uridines.
    supporting_text: The minimal binding site is a tract of six or more uridines within a
      9-13-nucleotide window.
  - statement: Nematode MEX proteins have diverged from the AU-rich-element specificity of
      mammalian TZF proteins via a single discriminator residue per zinc finger.
    supporting_text: We show that mutation of a single amino acid in each MEX-5 zinc finger
      confers tristetraprolin-like specificity to this protein.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Biochemistry characterizes MEX-5 specifically, not MEX-6. WormBase curated
      the mex-6 mRNA 3'-UTR binding IDA citing this paper from full text; MEX-6 is a
      near-identical TZF paralog so the class RNA-binding behaviour is expected to transfer,
      but no MEX-6-specific binding constants are published. Used here to justify MODIFY of
      the AU-rich/sequence-specific IBA terms.
- id: PMID:18199581
  title: Polo kinases regulate C. elegans embryonic polarity via binding to DYRK2-primed
    MEX-5 and MEX-6.
  findings:
  - statement: Polo kinases (PLK-1, PLK-2) bind MEX-5 and MEX-6 via their polo-box domains
      and regulate their activity.
    supporting_text: We show that polo kinases, via their polo box domains, bind to and
      regulate the activity of two key polarity proteins, MEX-5 and MEX-6.
  - statement: Asymmetric localization of the polo kinases depends on MEX-5 and MEX-6.
    supporting_text: This asymmetric localization of polo kinases depends on MEX-5 and
      MEX-6, as well as genes regulating MEX-5 and MEX-6 asymmetry.
  - statement: MBK-2/DYRK2 primes the polo-docking threonine (T186 in MEX-5) for polo
      kinase-dependent phosphorylation during the oocyte-to-embryo transition.
    supporting_text: We also show that MBK-2, a developmentally regulated DYRK2 kinase
      activated at meiosis II, primes T(186) for subsequent polo kinase-dependent
      phosphorylation.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Names MEX-6 explicitly and is the source of the mex-6 IPI (PLK-1/PLK-2,
      polo-box) and IGI (regulation of protein localization) annotations. In MEX-6 the
      primed residue is Thr-190 (UniProt MOD_RES 190; MUTAGEN T190A/T190E abolish PLK
      binding, ECO:0000269|PubMed:18199581). PubMed-verified; abstract-only in cache.
existing_annotations:
- term:
    id: GO:0035925
    label: mRNA 3'-UTR AU-rich region binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: This IBA is a phylogenetic transfer from the TTP/ZFP36 (tristetraprolin) family,
      whose members bind AU-rich elements (AREs). MEX-6 is a member of this CCCH TZF family
      (InterPro IPR045877 ZFP36-like), but the nematode MEX proteins have diverged from ARE
      specificity. Direct biochemistry on the near-identical paralog MEX-5 shows recognition
      of poly-uridine tracts with high affinity but low specificity, not the UUAUUUAUU ARE
      bound by mammalian TTP/ERF-2 (PMID:17264081).
    action: MODIFY
    reason: The AU-rich-element specificity implied by this term does not match the diverged
      binding behaviour of nematode MEX TZF proteins. In MEX-5, a single discriminator
      residue per zinc finger determines ARE vs poly-U preference, and wild-type MEX-5 binds
      poly-U promiscuously rather than AREs. There is no MEX-6-specific ARE-binding evidence.
      A more accurate and already experimentally supported term is mRNA 3'-UTR binding
      (GO:0003730), which is annotated with IDA for this gene.
    proposed_replacement_terms:
    - id: GO:0003730
      label: mRNA 3'-UTR binding
    additional_reference_ids:
    - PMID:17264081
    supported_by:
    - reference_id: PMID:17264081
      supporting_text: In contrast, human TZF homologs tristetraprolin and ERF-2 bind with
        high specificity to UUAUUUAUU elements.
    - reference_id: PMID:17264081
      supporting_text: We show that mutation of a single amino acid in each MEX-5 zinc finger
        confers tristetraprolin-like specificity to this protein.
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - FUNCTIONAL_DIVERGENCE
      source_entities:
      - source_id: PANTHER:PTN002648882
        source_label: TTP/ZFP36 CCCH-TZF family node
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: Ancestral ARE-binding specificity does not transfer; nematode MEX proteins
          diverged to low-specificity poly-U binding.
      - source_id: UniProtKB:P26651
        source_label: human ZFP36 (tristetraprolin)
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: Mammalian TTP binds UUAUUUAUU AREs with high specificity, unlike MEX-6.
- term:
    id: GO:0000289
    label: nuclear-transcribed mRNA poly(A) tail shortening
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: This IBA is inherited from the ancestral TTP/ZFP36 function of recruiting the
      deadenylase machinery to promote mRNA poly(A) tail shortening. There is no direct
      evidence that MEX-6 (or MEX-5) promotes deadenylation in C. elegans; the MEX-5/6
      literature concerns embryonic polarity and translational/RNP regulation, not mRNA
      decay.
    action: MARK_AS_OVER_ANNOTATED
    reason: Deadenylation is a well-established function of mammalian TTP-family paralogs but
      has not been demonstrated for MEX-6. The nematode MEX proteins have diverged in RNA
      specificity from their mammalian homologs (PMID:17264081), and the characterized
      MEX-5/6 outputs are on polarity determinants rather than bulk mRNA turnover. Retained
      as a family-level over-annotation without direct evidence.
    additional_reference_ids:
    - PMID:17264081
    supported_by:
    - reference_id: PMID:17264081
      supporting_text: In contrast, human TZF homologs tristetraprolin and ERF-2 bind with
        high specificity to UUAUUUAUU elements.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - FUNCTIONAL_DIVERGENCE
      source_entities:
      - source_id: PANTHER:PTN002648882
        source_label: TTP/ZFP36 CCCH-TZF family node
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: Mammalian TTP-family deadenylation is sound at the source but has no
          experimental support in MEX-6.
      - source_id: UniProtKB:P26651
        source_label: human ZFP36 (tristetraprolin)
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: TTP recruits the CCR4-NOT deadenylase; no such activity shown for MEX-6.
- term:
    id: GO:0000900
    label: mRNA regulatory element binding translation repressor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: This IBA proposes a sequence-specific translation-repressor activity by
      phylogenetic inference. MEX-6 does bind mRNA and, redundantly with MEX-5, controls the
      expression pattern of germline determinants, but the mechanism is not a clean
      sequence-specific translational repressor. The RNA binding of the paralog is
      low-specificity (PMID:17264081), and the best-characterized MEX-5/6 translational
      output (on the zif-1 3'UTR) is positive rather than repressive. No MEX-6-specific
      evidence establishes this molecular activity.
    action: UNDECIDED
    reason: The directionality and sequence-specificity implied by this term are not
      supported for MEX-6. Without direct evidence that MEX-6 functions as a sequence-specific
      translation repressor (as opposed to acting through low-specificity mRNA binding, mRNA
      competition, or positive regulation of specific targets), this annotation cannot be
      confidently accepted or removed and requires experimental clarification.
    additional_reference_ids:
    - PMID:17264081
    supported_by:
    - reference_id: PMID:17264081
      supporting_text: the TZF protein MEX-5, a primary anterior determinant, is an
        RNA-binding protein that recognizes linear RNA sequences with high affinity but
        low specificity
    propagation_review:
      root_cause: UNRESOLVED
      failure_modes:
      - FUNCTIONAL_DIVERGENCE
      - REGULATORY_SIGN_INVERSION
      source_entities:
      - source_id: PANTHER:PTN002648882
        source_label: TTP/ZFP36 CCCH-TZF family node
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: Repressor directionality is uncertain for MEX-6; the best-characterized
          MEX-5/6 translational output (zif-1 3'UTR) is positive, not repressive.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: MEX-6 is a cytoplasmic protein (UniProt SUBCELLULAR LOCATION Cytoplasm), imaged
      as a cytoplasmic GFP fusion in the early embryo (PMID:12588843) and consistent with the
      experimental IDA cytoplasm annotation. Cytosol is an appropriate active-location term
      for this non-membrane RNA-binding protein.
    action: ACCEPT
    reason: MEX-6 acts in the cytoplasm/cytosol of the zygote, where it forms an
      anterior-enriched pool and regulates cytoplasmic determinant asymmetry. Consistent with
      both experimental imaging and the phylogenetic inference.
    supported_by:
    - reference_id: PMID:12588843
      supporting_text: The kinase PAR-1 and the CCCH finger proteins MEX-5 and MEX-6 also
        function during the establishment phase in a feedback loop to regulate growth of
        the posterior domain.
- term:
    id: GO:0160134
    label: protein-RNA sequence-specific adaptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: This IBA implies MEX-6 acts as a sequence-specific adaptor between RNA and
      protein. MEX-6 binds mRNA and also binds protein partners (PLK-1/PLK-2 via polo-box
      docking), but its RNA binding is not sequence-specific - the near-identical paralog
      MEX-5 binds poly-U tracts with high affinity and low specificity (PMID:17264081).
    action: MODIFY
    reason: The "sequence-specific" qualifier of GO:0160134 is not supported for MEX-6, whose
      RNA recognition (by paralog inference) is promiscuous poly-U binding rather than a
      specific motif. The well-supported molecular activity is simply mRNA binding
      (GO:0003729); the protein-adaptor role toward polo kinases is captured separately by
      the protein kinase binding / protein domain specific binding annotations.
    proposed_replacement_terms:
    - id: GO:0003729
      label: mRNA binding
    additional_reference_ids:
    - PMID:17264081
    supported_by:
    - reference_id: PMID:17264081
      supporting_text: the TZF protein MEX-5, a primary anterior determinant, is an
        RNA-binding protein that recognizes linear RNA sequences with high affinity but
        low specificity
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
      - FUNCTIONAL_DIVERGENCE
      source_entities:
      - source_id: PANTHER:PTN002648882
        source_label: TTP/ZFP36 CCCH-TZF family node
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: The "sequence-specific" qualifier overstates MEX-6 RNA recognition, which
          by paralog inference is promiscuous poly-U binding.
- term:
    id: GO:0003729
    label: mRNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: MEX-6 contains two tandem C3H1-type CCCH zinc fingers (UniProt ZN_FING 273-302,
      317-347; InterPro IPR045877 ZFP36-like, IPR000571 CCCH), the RNA-binding module of the
      TTP/TZF family. mRNA binding is a core molecular function, independently supported by
      the experimental IDA for mRNA 3'-UTR binding (PMID:17264081, curated for mex-6).
    action: ACCEPT
    reason: mRNA binding is well supported for this gene by domain architecture and by the
      curated experimental 3'-UTR-binding annotation. Core molecular function.
    supported_by:
    - reference_id: PMID:17264081
      supporting_text: This sequence is remarkably abundant in the 3'-untranslated region
        of C. elegans transcripts
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Cytoplasmic localization inferred from the UniProt Swiss-Prot subcellular
      location. Consistent with the experimental IDA cytoplasm annotation (PMID:12588843) and
      UniProt SUBCELLULAR LOCATION Cytoplasm.
    action: ACCEPT
    reason: MEX-6 is a cytoplasmic protein; this location is corroborated by direct imaging in
      the early embryo. Correct, if generic relative to the anterior-enriched cytoplasmic
      pool.
    supported_by:
    - reference_id: PMID:12588843
      supporting_text: we have analyzed the localization dynamics of PAR-2, PAR-6, MEX-5,
        MEX-6 and PIE-1 in wild-type and mutant embryos
- term:
    id: GO:0017148
    label: negative regulation of translation
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: This IEA is a logical inference from GO:0000900 (mRNA regulatory element binding
      translation repressor activity), which is itself uncertain for MEX-6 (reviewed above as
      UNDECIDED). While MEX-5/6 restrict germline protein expression in the anterior, the
      mechanism is not established to be direct translational repression, and the
      best-characterized translational output (zif-1 3'UTR) is positive.
    action: UNDECIDED
    reason: Because the parent MF annotation (GO:0000900) is not confidently supported for
      MEX-6, the inferred negative-regulation-of-translation process term inherits that
      uncertainty. The directionality does not match the strongest published MEX-5/6
      translational mechanism. Requires direct evidence.
    additional_reference_ids:
    - PMID:10882103
    supported_by:
    - reference_id: PMID:10882103
      supporting_text: This network is required for subsequent asymmetries in the expression
        patterns of several proteins that are encoded by nonlocalized, maternally expressed
        mRNAs.
- term:
    id: GO:0043186
    label: P granule
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: This is a purely electronic ARBA machine-learning prediction of P-granule
      residency. MEX-6 is predominantly an anterior cytoplasmic protein, spatially
      anti-correlated with P granules, which segregate to the posterior. Any P-granule
      association (see the experimental IDA below) is at best transient and non-core; an
      unsupervised ARBA prediction is exactly the kind of electronic annotation to
      down-weight for a family whose members antagonize, rather than reside in, germ granules.
    action: KEEP_AS_NON_CORE
    reason: This electronic prediction is redundant with the experimental IDA to the same
      term (also kept non-core), so it is retained rather than removed, but marked non-core.
      MEX-6's core localization is the anterior cytoplasm, not stable structural residence in
      P granules, so P-granule localization should not be treated as a core function.
    supported_by:
    - reference_id: PMID:12588843
      supporting_text: The kinase PAR-1 and the CCCH finger proteins MEX-5 and MEX-6 also
        function during the establishment phase in a feedback loop to regulate growth of
        the posterior domain.
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: MEX-6 has two C3H1-type CCCH zinc fingers that each coordinate a zinc ion, the
      structural basis of its RNA-binding fold (UniProt ZN_FING; InterPro CCCH signatures).
      Metal ion binding is a correct, if generic, annotation.
    action: ACCEPT
    reason: Zinc coordination is intrinsic to the CCCH zinc-finger fold of MEX-6. Correct
      though non-specific; zinc ion binding (GO:0008270) would be the more precise term.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Cytoplasmic localization transferred by sequence similarity from the paralog
      MEX-5 (UniProtKB:Q9XUB2). This ortholog/paralog transfer is consistent with the
      independent experimental IDA (PMID:12588843) and with UniProt's Cytoplasm assignment.
    action: ACCEPT
    reason: The cytoplasm location is correct for MEX-6 and is corroborated by direct
      experimental evidence, so the ISS transfer from MEX-5 is appropriate.
    supported_by:
    - reference_id: PMID:12588843
      supporting_text: we have analyzed the localization dynamics of PAR-2, PAR-6, MEX-5,
        MEX-6 and PIE-1 in wild-type and mutant embryos
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IPI
  original_reference_id: PMID:18199581
  qualifier: enables
  review:
    summary: PMID:18199581 demonstrates that the Polo-like kinases PLK-1 and PLK-2 bind
      directly to MEX-6 (named explicitly) via their polo-box domains, dependent on
      MBK-2/DYRK2-primed phosphorylation of the polo-docking threonine (Thr-190 in MEX-6;
      UniProt MOD_RES 190, MUTAGEN T190A/T190E abolish PLK binding). Curated by WormBase with
      plk-1 (WBGene00004042) and plk-2 (WBGene00004043) as interactors.
    action: ACCEPT
    reason: Direct experimental protein-kinase-binding evidence naming MEX-6; functionally
      important for embryonic polarity. Core interaction.
    supported_by:
    - reference_id: PMID:18199581
      supporting_text: We show that polo kinases, via their polo box domains, bind to and
        regulate the activity of two key polarity proteins, MEX-5 and MEX-6.
- term:
    id: GO:0019904
    label: protein domain specific binding
  evidence_type: IPI
  original_reference_id: PMID:18199581
  qualifier: enables
  review:
    summary: MEX-6 binds specifically to the polo-box domains of PLK-1 and PLK-2 (a
      phosphopeptide-docking domain), a bona fide domain-specific protein interaction
      (PMID:18199581), primed by MBK-2 phosphorylation at Thr-190.
    action: ACCEPT
    reason: The interaction is with a defined protein domain (the polo-box domain), directly
      demonstrated for MEX-6. Supports protein domain specific binding.
    supported_by:
    - reference_id: PMID:18199581
      supporting_text: We show that polo kinases, via their polo box domains, bind to and
        regulate the activity of two key polarity proteins, MEX-5 and MEX-6.
- term:
    id: GO:0032880
    label: regulation of protein localization
  evidence_type: IGI
  original_reference_id: PMID:18199581
  qualifier: involved_in
  review:
    summary: MEX-6, redundantly with MEX-5 (genetic interaction; WormBase with = mex-5
      WBGene00003230), is required for the asymmetric localization of downstream determinants.
      Removing MEX-5 and MEX-6 disrupts asymmetric distribution of PLK-1 (and PIE-1, MEX-1,
      POS-1); UniProt DISRUPTION PHENOTYPE notes that mex-6 RNAi in a mex-5(zu199) background
      causes loss of plk-1 asymmetry (PMID:18199581). The polo kinases' asymmetric
      localization depends on MEX-5 and MEX-6.
    action: ACCEPT
    reason: Regulation of the asymmetric localization of germline/polarity determinants is a
      core, experimentally supported biological process for the MEX-5/MEX-6 pair, with the
      genetic-interaction evidence specifically implicating mex-6 in a mex-5-sensitized
      background.
    supported_by:
    - reference_id: PMID:18199581
      supporting_text: This asymmetric localization of polo kinases depends on MEX-5 and
        MEX-6, as well as genes regulating MEX-5 and MEX-6 asymmetry.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:12588843
  qualifier: located_in
  review:
    summary: Direct experimental (IDA, WormBase) cytoplasmic localization of MEX-6, imaged as
      a GFP fusion during zygote polarization (PMID:12588843). This is the primary-evidence
      cytoplasm annotation.
    action: ACCEPT
    reason: Direct observation of cytoplasmic MEX-6 in the early embryo; the core cellular
      location of the protein.
    supported_by:
    - reference_id: PMID:12588843
      supporting_text: we have analyzed the localization dynamics of PAR-2, PAR-6, MEX-5,
        MEX-6 and PIE-1 in wild-type and mutant embryos
- term:
    id: GO:0043186
    label: P granule
  evidence_type: IDA
  original_reference_id: PMID:12588843
  qualifier: located_in
  review:
    summary: WormBase curated an experimental (IDA) P-granule localization for MEX-6 from the
      full text of PMID:12588843 (a live-imaging study of MEX-6 and other polarity factors).
      The cached abstract does not itself mention P granules, so I cannot independently verify
      the observation, but I defer to the curator's reading of the full text. Biologically,
      MEX-6 is predominantly anterior cytoplasmic (where P granules are depleted), so any
      P-granule association is transient/minor rather than a core residence - unlike bona fide
      P-granule scaffolds. The near-identical paralog MEX-5 has been shown to antagonize
      (dissolve) rather than reside in P granules, but no equivalent phase-separation study
      exists for MEX-6.
    action: KEEP_AS_NON_CORE
    reason: This is an experimental annotation whose supporting full text I cannot see; per
      project guidelines I do not REMOVE it on the basis of an abstract that foregrounds
      other observations. However, given MEX-6's anterior-cytoplasmic enrichment and the lack
      of evidence that it is a structural P-granule component, the localization is retained as
      non-core rather than as a core function.
    supported_by:
    - reference_id: PMID:12588843
      supporting_text: we have analyzed the localization dynamics of PAR-2, PAR-6, MEX-5,
        MEX-6 and PIE-1 in wild-type and mutant embryos
- term:
    id: GO:0003730
    label: mRNA 3'-UTR binding
  evidence_type: IDA
  original_reference_id: PMID:17264081
  qualifier: enables
  review:
    summary: WormBase curated an experimental (IDA) mRNA 3'-UTR-binding activity for MEX-6
      citing PMID:17264081. That paper's abstract characterizes the biochemistry of the
      near-identical paralog MEX-5 (poly-U tracts abundant in C. elegans 3'-UTRs); the mex-6
      IDA reflects the curator's reading of the full text. MEX-6 has the same tandem CCCH
      zinc-finger RNA-binding module, so 3'-UTR binding is biologically expected.
    action: ACCEPT
    reason: mRNA 3'-UTR binding is a genuine, core molecular function of this TZF protein and
      is curated as experimental for mex-6. Per project guidelines I defer to the curator
      rather than REMOVE an experimental annotation because the cached abstract foregrounds
      the paralog MEX-5.
    supported_by:
    - reference_id: PMID:17264081
      supporting_text: This sequence is remarkably abundant in the 3'-untranslated region
        of C. elegans transcripts
- term:
    id: GO:0008595
    label: anterior/posterior axis specification, embryo
  evidence_type: IMP
  original_reference_id: PMID:10882103
  qualifier: involved_in
  review:
    summary: MEX-6, redundantly with MEX-5, links cortical PAR polarity to soma/germline
      asymmetry along the anterior-posterior axis of the early embryo (PMID:10882103,
      PMID:12588843). This biological process is not present in the current GOA for mex-6 but
      is a core role of the MEX-5/MEX-6 pair.
    action: NEW
    reason: Anterior-posterior axis specification is a core developmental process for the
      MEX-5/MEX-6 pair, with MEX-6 contributing redundantly with MEX-5. Added as a proposed
      new annotation to reflect this core function.
    supported_by:
    - reference_id: PMID:10882103
      supporting_text: We provide evidence that two nearly identical genes, mex-5 and mex-6,
        link PAR asymmetry to those subsequent protein asymmetries.
    - reference_id: PMID:12588843
      supporting_text: Polarization of the C. elegans zygote along the anterior-posterior
        axis depends on cortically enriched (PAR) and cytoplasmic (MEX-5/6) proteins
core_functions:
- description: MEX-6 binds maternal mRNA 3'-UTRs through its tandem CCCH zinc fingers and,
    redundantly with MEX-5, converts cortical PAR polarity into cytoplasmic soma/germline
    asymmetry, patterning the distribution of germline determinants (PIE-1, POS-1, MEX-1)
    along the anterior-posterior axis of the early embryo.
  molecular_function:
    id: GO:0003730
    label: mRNA 3'-UTR binding
  directly_involved_in:
  - id: GO:0008595
    label: anterior/posterior axis specification, embryo
  - id: GO:0032880
    label: regulation of protein localization
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:10882103
    supporting_text: We provide evidence that two nearly identical genes, mex-5 and mex-6,
      link PAR asymmetry to those subsequent protein asymmetries.
  - reference_id: PMID:17264081
    supporting_text: This sequence is remarkably abundant in the 3'-untranslated region
      of C. elegans transcripts
- description: MEX-6 acts as a substrate and adaptor for the Polo-like kinases PLK-1 and
    PLK-2, binding their polo-box domains via an MBK-2/DYRK2-primed phosphothreonine
    (Thr-190); this interaction is required (with MEX-5) for the anterior enrichment of
    PLK-1/PLK-2 and their control of determinant asymmetry.
  molecular_function:
    id: GO:0019901
    label: protein kinase binding
  directly_involved_in:
  - id: GO:0032880
    label: regulation of protein localization
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:18199581
    supporting_text: We show that polo kinases, via their polo box domains, bind to and
      regulate the activity of two key polarity proteins, MEX-5 and MEX-6.
  - reference_id: PMID:18199581
    supporting_text: This asymmetric localization of polo kinases depends on MEX-5 and
      MEX-6, as well as genes regulating MEX-5 and MEX-6 asymmetry.
proposed_new_terms: []
suggested_questions:
- question: Does MEX-6 have any non-redundant function, target mRNA, tissue, or developmental
    timing distinct from MEX-5, or is it a purely redundant backup copy?
  experts:
  - Lin R
  - Priess JR
- question: Is the RNA-binding activity of MEX-6 required for its role in embryonic polarity,
    and does MEX-6 (like MEX-5) bind poly-U tracts with low sequence specificity?
  experts:
  - Ryder SP
suggested_experiments:
- description: Perform iCLIP/CLIP-seq on endogenously tagged MEX-6 in early embryos to define
    its direct mRNA targets genome-wide and compare them to MEX-5 targets, testing whether
    MEX-6 has any private target repertoire.
  hypothesis: MEX-6 binds essentially the same poly-U-rich 3'-UTR set as MEX-5, consistent
    with full functional redundancy.
- description: Generate RNA-binding-deficient MEX-6 zinc-finger mutants at the endogenous
    locus in a mex-5 null background and assay embryonic viability and PLK-1/PIE-1 asymmetry,
    to test whether MEX-6 RNA binding is required for its polarity function.
  hypothesis: MEX-6 RNA binding is required for anterior enrichment and for establishing
    determinant asymmetry when MEX-5 is absent.
- description: Live-image endogenously tagged MEX-6 together with a P-granule marker (e.g.
    PGL-1) to determine whether the curated P-granule signal reflects stable residence or
    transient association, and whether MEX-6 promotes anterior P-granule dissolution as
    reported for MEX-5.
  hypothesis: MEX-6 is anterior-enriched and only transiently overlaps P granules, mirroring
    the P-granule-antagonizing behaviour of MEX-5.
knowledge_gaps:
- gap_statement: The non-redundant, MEX-6-specific contribution to embryonic polarity is
    undefined. It is unknown whether MEX-6 has any private target mRNA, tissue, developmental
    timing, or molecular activity distinct from its near-identical paralog MEX-5, or whether
    it is a functionally interchangeable backup copy.
  boundary: It is firmly established that mex-5 and mex-6 are nearly identical genes that act
    together to link PAR asymmetry to downstream determinant asymmetries, and that the mex-6
    contribution is exposed genetically only in a mex-5-sensitized background (mex-6 RNAi in
    mex-5(zu199) causes loss of PLK-1 asymmetry). MEX-5 is consistently the dominant,
    better-characterized paralog.
  gap_kind:
  - BIOLOGY
  dark_aspect: RESIDUAL_SUBGAP
  status: OPEN
  significance: Distinguishing genuine redundancy from division of labor is central to
    understanding the robustness of the soma/germline decision and whether MEX-6 is a
    dispensable paralog or a buffer with its own regulatory inputs.
  resolution: Endogenous single- and double-null comparisons with quantitative determinant
    readouts, plus paralog-specific CLIP-seq, to test for any MEX-6-only target or phenotype.
  provenance:
  - reference_id: PMID:10882103
    supporting_text: We provide evidence that two nearly identical genes, mex-5 and mex-6,
      link PAR asymmetry to those subsequent protein asymmetries.
    reference_section_type: ABSTRACT
- gap_statement: The direct mRNA targets of MEX-6 and its RNA-binding specificity have not
    been determined for MEX-6 itself. All biochemical RNA-recognition data (poly-U tract,
    high affinity, low specificity, discriminator residue) come from the paralog MEX-5.
  boundary: MEX-6 has two tandem C3H1-type CCCH zinc fingers of the TTP/ZFP36 family and a
    curated experimental mRNA 3'-UTR-binding activity, so it is an mRNA-binding protein; but
    no MEX-6-specific binding constants, motif, or target set are published, and even for
    MEX-5 the field notes that its binding cannot by itself specify target selection.
  gap_kind:
  - BIOLOGY
  dark_aspect: MF_DARK
  status: OPEN
  significance: Without direct MEX-6 targets it is impossible to assign a specific molecular
    mechanism (repression, competition, stabilization) to the polarity phenotype, leaving
    MEX-6 mechanistically dark despite a well-defined developmental role.
  resolution: MEX-6-specific in vitro binding measurements and in vivo CLIP-seq to define the
    motif preference and target set directly.
  provenance:
  - reference_id: PMID:17264081
    supporting_text: This sequence is remarkably abundant in the 3'-untranslated region of
      C. elegans transcripts, demonstrating that MEX-5 alone cannot specify mRNA target
      selection.
    reference_section_type: ABSTRACT
- gap_statement: Whether MEX-6 RNA binding is required for its function in anterior-posterior
    polarity is untested for MEX-6. It is unknown whether zinc-finger/RNA-binding-dead MEX-6
    can still form an anterior gradient, dock PLK-1/PLK-2, and support determinant asymmetry
    when MEX-5 is absent.
  boundary: The polo-docking arm of MEX-6 function is well mapped (MBK-2-primed Thr-190,
    polo-box binding, requirement for PLK-1/PLK-2 asymmetry), and the RNA-binding-to-polarity
    link has been argued for MEX-5; but no separation-of-function RNA-binding mutant of MEX-6
    has been assayed in vivo.
  gap_kind:
  - BIOLOGY
  dark_aspect: RESIDUAL_SUBGAP
  status: OPEN
  significance: This determines whether MEX-6's essential activity is RNA-binding, a
    protein-scaffold (polo-adaptor) role, or both, and therefore which molecular function
    should anchor its polarity annotation.
  resolution: Endogenous RNA-binding-deficient MEX-6 zinc-finger mutants assayed in a mex-5
    null background for gradient formation, PLK-1 docking, and determinant asymmetry.
  provenance:
  - reference_id: PMID:18199581
    supporting_text: We show that polo kinases, via their polo box domains, bind to and
      regulate the activity of two key polarity proteins, MEX-5 and MEX-6.
    reference_section_type: ABSTRACT
tags:
- caeel-p-granules