id: Q14576
gene_symbol: ELAVL3
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: ELAVL3 (HuC) is a neuron-specific RNA-binding protein with three RNA
  recognition motifs (RRMs) and a hinge/linker region that binds to AU-/U-rich elements
  in the 3'-UTRs of target mRNAs to regulate mRNA stability, alternative splicing,
  alternative polyadenylation (3'-UTR length choice), and transcript abundance. RRM1
  and RRM2 directly associate with AU-rich RNA, while RRM3 promotes transcript stability
  via poly(A)-tail-associated mechanisms. ELAVL3 is predominantly cytoplasmic but
  shuttles between nucleus and cytoplasm via signals in the hinge region. It plays
  essential roles in neuronal differentiation, maintenance, and synaptic integrity,
  particularly in the cerebellum and hippocampus; ELAVL3 loss perturbs splicing programs
  converging on glutamate regulation and neuronal excitability (e.g., AnkG exon 34
  mis-inclusion), producing seizures and cerebellar ataxia in knockout models.
existing_annotations:
- term:
    id: GO:0140517
    label: protein-RNA adaptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IBA annotation for protein-RNA adaptor activity based on phylogenetic
      inference. ELAVL3 functions as an RNA-binding protein that binds AU-rich elements
      in 3'-UTRs and regulates mRNA stability and processing, consistent with adaptor
      activity.
    action: ACCEPT
    reason: This term accurately captures ELAVL3's core molecular function as a protein
      that mediates interactions between RNA molecules and other cellular components
      through its RNA-binding activity. The deep research confirms ELAVL3 "binds preferentially
      to GU-rich and AU-rich sequences in intronic regions and 3'-untranslated regions
      (3'-UTRs) of target pre-mRNAs" and "regulates alternative splicing, mRNA stability,
      and transcript abundance". UniProt confirms it "binds to AU-rich element (ARE)
      sequences of target mRNAs" [PMID:10710437]. IBA annotations are typically well-curated
      and phylogenetically sound.
    supported_by:
    - reference_id: PMID:10710437
      supporting_text: HuC and HuD bind to the VEGF 3'-UTR regulatory segment (VRS)
        and to the c- myc 3'-UTR in a specific and concentration-dependent pattern
    - reference_id: file:human/ELAVL3/ELAVL3-deep-research-perplexity-lite.md
      supporting_text: ELAVL3 binds preferentially to GU-rich and AU-rich sequences
        in intronic regions and 3'-untranslated regions (3'-UTRs) of target pre-mRNAs.
        This binding regulates alternative splicing, mRNA stability, and transcript
        abundance
    - reference_id: file:human/ELAVL3/ELAVL3-deep-research-falcon.md
      supporting_text: ELAVL3 functions primarily as a post-transcriptional regulator
        that stabilizes target transcripts, in part by binding AU-rich elements and
        influencing poly(A)-tail-associated protection; ELAVL proteins can multimerize
        on RNA and oppose destabilizing factors.
    - reference_id: PMID:37697079
      supporting_text: Binding to RNA targets is facilitated by the RRM1 and RRM2
        domains preferentially recognising AU-rich elements in the 3ʹUTR of transcripts
- term:
    id: GO:0003676
    label: nucleic acid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: IEA annotation for nucleic acid binding based on InterPro domain assignment.
      This is a very general parent term for RNA binding.
    action: MODIFY
    reason: While technically correct (ELAVL3 does bind nucleic acids), this term
      is too broad and uninformative. ELAVL3 specifically binds RNA, not DNA, through
      its three RRM domains. The more specific term GO:0003723 (RNA binding) is already
      annotated and better represents the actual molecular function.
    proposed_replacement_terms:
    - id: GO:0003723
      label: RNA binding
    supported_by:
    - reference_id: file:human/ELAVL3/ELAVL3-deep-research-perplexity-lite.md
      supporting_text: ELAVL3 contains three RNP-type RNA recognition motifs (RRMs),
        which are responsible for its RNA-binding activity
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation for RNA binding from combined automated annotation methods.
      This is appropriate but less specific than the available AU-rich region binding
      terms.
    action: ACCEPT
    reason: This term accurately describes ELAVL3's core molecular function. ELAVL3
      contains three RRM domains that bind RNA, specifically to AU-rich and GU-rich
      sequences in mRNA 3'-UTRs. While more specific terms exist (mRNA 3'-UTR AU-rich
      region binding), this general RNA binding term is acceptable and correct as
      a broader classification.
    supported_by:
    - reference_id: PMID:10710437
      supporting_text: These proteins bind to AU-rich elements in the 3'-untranslated
        regions (3'-UTRs) of many growth-related mRNAs, including c-myc and VEGF
    - reference_id: file:human/ELAVL3/ELAVL3-deep-research-perplexity-lite.md
      supporting_text: ELAVL3 contains three RNP-type RNA recognition motifs (RRMs),
        which are responsible for its RNA-binding activity
    - reference_id: PMID:37697079
      supporting_text: All four ELAVL proteins share a common basic structure, of
        three RNA recognition motif (RRM) binding domains and a hinge region
- term:
    id: GO:0003730
    label: mRNA 3'-UTR binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: IEA annotation for mRNA 3'-UTR binding from ARBA machine learning models.
      This accurately captures ELAVL3's specific binding preference for 3'-UTR regions.
    action: ACCEPT
    reason: This is a highly specific and accurate molecular function term for ELAVL3.
      Multiple lines of evidence demonstrate that ELAVL3 preferentially binds to AU-rich
      elements located in the 3'-UTRs of target mRNAs including VEGF and c-myc. This
      is a core molecular function of the protein.
    supported_by:
    - reference_id: PMID:10710437
      supporting_text: HuC and HuD bind to the VEGF 3'-UTR regulatory segment (VRS)
        and to the c- myc 3'-UTR in a specific and concentration-dependent pattern
    - reference_id: file:human/ELAVL3/ELAVL3-deep-research-perplexity-lite.md
      supporting_text: ELAVL3 binds preferentially to GU-rich and AU-rich sequences
        in intronic regions and 3'-untranslated regions (3'-UTRs) of target pre-mRNAs
- term:
    id: GO:0007399
    label: nervous system development
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: IEA annotation for nervous system development based on UniProtKB keyword
      mapping. ELAVL3 is neuron-specific and plays roles in neuronal differentiation
      and maintenance.
    action: ACCEPT
    reason: This biological process term is well-supported. ELAVL3 is brain-specific
      and essential for neurogenesis, neuronal differentiation, and maintenance of
      neurons. The deep research indicates ELAVL3 is "involved in the development
      and maintenance of neurons" and knockout mice exhibit severe motor deficits
      and cerebellar ataxia. UniProt states it "may be involved in neuronal differentiation
      and maintenance".
    supported_by:
    - reference_id: file:human/ELAVL3/ELAVL3-deep-research-perplexity-lite.md
      supporting_text: 'Neurogenesis: ELAVL3 is involved in the development and maintenance
        of neurons'
    - reference_id: file:human/ELAVL3/ELAVL3-deep-research-perplexity-lite.md
      supporting_text: ELAVL3 knockout mice exhibit progressive motor deficits, severe
        cerebellar ataxia, and Purkinje cell axonal degeneration
    - reference_id: PMID:37697079
      supporting_text: As Elavl3−/− mice aged, progressive severe cerebellar ataxia
        was observed
    - reference_id: PMID:37697079
      supporting_text: At the cellular level, Purkinje neurons had disrupted synaptic
        formation, swollen axons, and overall deficits in neuronal transport, highlighting
        the requirement for Elavl3 activity in these neurons
- term:
    id: GO:0030154
    label: cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: IEA annotation for cell differentiation based on UniProtKB keyword mapping.
      This is a very general process term that applies to ELAVL3's role in neuronal
      differentiation.
    action: MODIFY
    reason: While technically correct (ELAVL3 is involved in neuronal differentiation),
      this term is too broad and non-specific. The more precise term would be neuronal
      differentiation or neuron differentiation, which better captures ELAVL3's tissue-specific
      role. Given that ELAVL3 is brain-specific and specifically involved in neurogenesis,
      a more specific term should be used.
    proposed_replacement_terms:
    - id: GO:0030182
      label: neuron differentiation
    supported_by:
    - reference_id: file:human/ELAVL3/ELAVL3-deep-research-perplexity-lite.md
      supporting_text: 'Neurogenesis: ELAVL3 is involved in the development and maintenance
        of neurons'
    - reference_id: PMID:37697079
      supporting_text: Elavl3 expression is upregulated during the differentiation
        of neural stem cells into inhibitory GABAergic neurons, in parallel with 3’UTR
        lengthening. Depletion of Elavl3 during this differentiation process caused
        a shift towards using proximal polyA sites compared to control cells, with
        a concomitant delay in neural stem cell differentiation
- term:
    id: GO:1990904
    label: ribonucleoprotein complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: IEA annotation for ribonucleoprotein complex based on InterPro domain
      assignment. This cellular component term reflects ELAVL3's association with
      RNA as an RNP complex component.
    action: ACCEPT
    reason: This is an appropriate cellular component annotation. ELAVL3 is an RNA-binding
      protein with RRM domains that forms ribonucleoprotein complexes with its target
      mRNAs. The deep research notes ELAVL3 binds over 1,100 transcripts in certain
      contexts, indicating it forms functional RNP complexes. While more specific
      localization terms could be added (nucleus, cytoplasm), this general RNP complex
      annotation is correct.
    supported_by:
    - reference_id: file:human/ELAVL3/ELAVL3-deep-research-perplexity-lite.md
      supporting_text: In neuroendocrine cancer cell lines, ELAVL3 binds over 1,100
        transcripts, with enrichment for genes involved in neuron projection development
        and synapse organization
    - reference_id: file:human/ELAVL3/ELAVL3-deep-research-perplexity-lite.md
      supporting_text: ELAVL3 is predominantly localized in the nucleus and cytoplasm
        of neurons throughout the brain
- term:
    id: GO:0035925
    label: mRNA 3'-UTR AU-rich region binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation for mRNA 3'-UTR AU-rich region binding from Ensembl Compara
      orthology transfer. This is the most specific and accurate molecular function
      term for ELAVL3.
    action: ACCEPT
    reason: This is the most precise molecular function annotation for ELAVL3 and
      represents its core biochemical activity. ELAVL3 specifically binds to AU-rich
      elements (AREs) in the 3'-UTRs of target mRNAs. PMID:10710437 experimentally
      demonstrates HuC binding to AU-rich regions in VEGF and c-myc 3'-UTRs. The deep
      research confirms binding to "GU-rich and AU-rich sequences" in 3'-UTRs. This
      annotation captures the key sequence specificity that distinguishes ELAVL3 from
      general RNA-binding proteins.
    supported_by:
    - reference_id: PMID:10710437
      supporting_text: These proteins bind to AU-rich elements in the 3'-untranslated
        regions (3'-UTRs) of many growth-related mRNAs, including c-myc and VEGF
    - reference_id: file:human/ELAVL3/ELAVL3-deep-research-perplexity-lite.md
      supporting_text: ELAVL3 binds preferentially to GU-rich and AU-rich sequences
        in intronic regions and 3'-untranslated regions (3'-UTRs) of target pre-mRNAs
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36950384
  review:
    summary: IPI annotation for protein binding based on physical interaction evidence
      from a large-scale proteomics study on autism spectrum disorders.
    action: REMOVE
    reason: While ELAVL3 does interact with proteins (UniProt mentions MAP1B light
      chain LC1, and IntAct shows interactions with DYRK1A, SCN2A, SYNGAP1), the generic
      "protein binding" term is uninformative and does not describe a molecular function.
      This term should not be used unless referring to a specific functional role
      (e.g., as an adapter or scaffold). The reference PMID:36950384 is a large-scale
      protein interaction study where ELAVL3 may have been detected as an interactor,
      but this does not constitute evidence for "protein binding" as a molecular function.
      ELAVL3's primary molecular function is RNA binding, not protein binding.
    supported_by:
    - reference_id: file:human/ELAVL3/ELAVL3-deep-research-perplexity-lite.md
      supporting_text: "Molecular Function: ELAVL3 binds preferentially to GU-rich\
        \ and AU-rich sequences in intronic regions and 3'-untranslated regions (3'-UTRs)\
        \ of target pre-mRNAs"
    - reference_id: PMID:36950384
      supporting_text: eCollection 2023 Mar 8.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:37207277
  review:
    summary: IPI annotation for protein binding based on physical interaction evidence
      from a large-scale brain cell-type-specific protein interactome study on schizophrenia.
    action: REMOVE
    reason: Same rationale as for PMID:36950384. The generic "protein binding" term
      is uninformative and should be avoided in GO curation. While ELAVL3 does engage
      in protein-protein interactions, this is not its primary molecular function,
      and the term does not provide useful functional information. ELAVL3 is fundamentally
      an RNA-binding protein. Large-scale proteomics studies detect many interactions,
      but these do not necessarily represent the core molecular function of the protein.
    supported_by:
    - reference_id: file:human/ELAVL3/ELAVL3-deep-research-perplexity-lite.md
      supporting_text: "Molecular Function: ELAVL3 binds preferentially to GU-rich\
        \ and AU-rich sequences in intronic regions and 3'-untranslated regions (3'-UTRs)\
        \ of target pre-mRNAs"
    - reference_id: PMID:37207277
      supporting_text: eCollection 2023 May 19.
- term:
    id: GO:0035925
    label: mRNA 3'-UTR AU-rich region binding
  evidence_type: IDA
  original_reference_id: PMID:10710437
  review:
    summary: IDA annotation for mRNA 3'-UTR AU-rich region binding based on direct
      experimental evidence from PMID:10710437. This is a duplicate of the IEA annotation
      but with stronger experimental evidence.
    action: ACCEPT
    reason: This is the gold standard annotation for ELAVL3 - direct experimental
      evidence (IDA) for its most specific and important molecular function. PMID:10710437
      directly demonstrates using an ELISA-based assay that HuC (ELAVL3) binds to
      AU-rich elements in the 3'-UTRs of VEGF and c-myc mRNAs in a specific and concentration-dependent
      manner. This represents the core biochemical activity of ELAVL3. The experimental
      evidence is robust and the term is maximally informative.
    supported_by:
    - reference_id: PMID:10710437
      supporting_text: I demonstrate that HuC and HuD bind to the VEGF 3'-UTR regulatory
        segment (VRS) and to the c- myc 3'-UTR in a specific and concentration-dependent
        pattern
    - reference_id: PMID:10710437
      supporting_text: These proteins bind to AU-rich elements in the 3'-untranslated
        regions (3'-UTRs) of many growth-related mRNAs, including c-myc and VEGF
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations. ELAVL3 has a smaller
      nuclear pool that supports roles in splicing and APA, consistent with nucleocytoplasmic
      shuttling driven by hinge-region signals.
    supported_by:
    - reference_id: file:human/ELAVL3/ELAVL3-deep-research-perplexity-lite.md
      supporting_text: ELAVL3 is involved in the development and maintenance of neurons.
        ELAVL3 binds over 1,100 transcripts in neuroendocrine cancer cell lines, with
        enrichment for genes involved in neuron projection development and synapse
        organization
    - reference_id: UniProtKB:Q14576
      supporting_text: May be involved in neuronal differentiation and maintenance
        (By similarity).
    - reference_id: file:human/ELAVL3/ELAVL3-deep-research-falcon.md
      supporting_text: ELAVL3 is predominantly cytoplasmic but capable of nucleocytoplasmic
        shuttling. A smaller nuclear pool supports roles in splicing and RNA processing,
        while the hinge/linker region contributes to export/localization control.
    - reference_id: PMID:37697079
      supporting_text: Nuclear export and localisation signals located in the hinge
        region of the ELAVL proteins are responsible for the shuttling of RNAs between
        the nucleus and cytoplasm
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations. nELAVL proteins
      including ELAVL3 are predominantly cytoplasmic where they participate in cytoplasmic
      mRNA stability and translation control.
    supported_by:
    - reference_id: file:human/ELAVL3/ELAVL3-deep-research-perplexity-lite.md
      supporting_text: ELAVL3 is involved in the development and maintenance of neurons.
        ELAVL3 binds over 1,100 transcripts in neuroendocrine cancer cell lines, with
        enrichment for genes involved in neuron projection development and synapse
        organization
    - reference_id: UniProtKB:Q14576
      supporting_text: May be involved in neuronal differentiation and maintenance
        (By similarity).
    - reference_id: PMID:37697079
      supporting_text: nELAVL proteins are primarily cytoplasmic, with a small fraction
        of nuclear activity, reflecting their roles (for example nuclear export, subcellular
        shuttling)
    - reference_id: file:human/ELAVL3/ELAVL3-deep-research-falcon.md
      supporting_text: ELAVL3 is predominantly cytoplasmic but capable of nucleocytoplasmic
        shuttling.
- term:
    id: GO:0010608
    label: post-transcriptional regulation of gene expression
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations. Falcon-cited literature
      reinforces ELAVL3's role as a post-transcriptional regulator controlling splicing,
      APA/3'-UTR length choice, mRNA stability and translation.
    supported_by:
    - reference_id: file:human/ELAVL3/ELAVL3-deep-research-perplexity-lite.md
      supporting_text: ELAVL3 is involved in the development and maintenance of neurons.
        ELAVL3 binds over 1,100 transcripts in neuroendocrine cancer cell lines, with
        enrichment for genes involved in neuron projection development and synapse
        organization
    - reference_id: UniProtKB:Q14576
      supporting_text: May be involved in neuronal differentiation and maintenance
        (By similarity).
    - reference_id: PMID:37697079
      supporting_text: RNA-binding proteins (RBPs) are recognised as key regulators
        of post-transcriptional gene regulation, where their binding controls splicing,
        polyadenylation, nuclear export, mRNA stability and translation rate and decay
- term:
    id: GO:0000380
    label: alternative mRNA splicing, via spliceosome
  evidence_type: NAS
  review:
    summary: Added based on falcon-cited literature documenting ELAVL3 regulation
      of neuronal alternative splicing programs.
    action: NEW
    reason: Falcon and Mulligan 2023 (PMID:37697079) document that ELAVL3 regulates
      alternative splicing of neuronal transcripts (e.g., AnkG/ANK3 exon 34) with
      convergence on glutamate-regulation and excitability pathways. This is a core
      molecular process not previously captured in existing_annotations.
    supported_by:
    - reference_id: PMID:37697079
      supporting_text: Elavl3 regulates the embryonic-specific inclusion of vertebrate-specific
        exon 34 in the AnkG transcript.
    - reference_id: PMID:37697079
      supporting_text: High-throughput sequencing analysis of alternative splicing
        in the cerebellum of Elavl3−/− mice highlighted the convergence of targeted
        transcripts on glutamate levels and neuronal excitability
    - reference_id: file:human/ELAVL3/ELAVL3-deep-research-falcon.md
      supporting_text: ELAVL3 has a documented role in alternative splicing; all three
        RRMs plus the hinge region contribute to HuC-dependent splice regulation,
        and ELAVL3 loss alters neuronal splicing programs linked to excitability.
- term:
    id: GO:0110104
    label: mRNA alternative polyadenylation
  evidence_type: NAS
  review:
    summary: Added based on falcon-cited literature documenting ELAVL3 regulation
      of alternative polyadenylation and 3'-UTR length choice in neurons.
    action: NEW
    reason: Multiple sources cited by falcon (Mulligan 2023 PMID:37697079; Dorrity
      2023 PMID:37862432) demonstrate that ELAVL3 (with other nELAVLs) promotes neuronal
      3'-UTR lengthening through distal poly(A) site usage; ELAVL3 depletion shifts
      usage toward proximal sites. This is a distinct molecular process from splicing/stability
      and warrants a separate annotation.
    supported_by:
    - reference_id: PMID:37697079
      supporting_text: Depletion of Elavl3 during this differentiation process caused
        a shift towards using proximal polyA sites compared to control cells, with
        a concomitant delay in neural stem cell differentiation
    - reference_id: PMID:37862432
      supporting_text: the neuron-enriched ELAVL family of genes (ELAVL2, ELAVL3,
        and ELAVL4) can increase (i) 3'UTR length, (ii) dsRNA load, and (iii) activation
        of dsRNA-sensing PRRs such as MDA5, PKR, and TLR3
    - reference_id: file:human/ELAVL3/ELAVL3-deep-research-falcon.md
      supporting_text: ELAVL3 participates in regulation of alternative polyadenylation
        and 3′UTR length in neurons. ELAVL3 depletion shifts usage toward proximal
        poly(A) sites, whereas neuronal ELAVL proteins promote longer neuronal 3′UTRs.
- term:
    id: GO:0003729
    label: mRNA binding
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations. ELAVL3 binds mRNA
      via three RRM domains; this captures the molecular function used to regulate
      splicing/APA/stability of target mRNAs.
    supported_by:
    - reference_id: PMID:37697079
      supporting_text: All four ELAVL proteins share a common basic structure, of
        three RNA recognition motif (RRM) binding domains and a hinge region
    - reference_id: PMID:37697079
      supporting_text: Binding to RNA targets is facilitated by the RRM1 and RRM2
        domains preferentially recognising AU-rich elements in the 3ʹUTR of transcripts
# GO:0048167 (regulation of synaptic plasticity) NEW annotation REMOVED
# per PR #684 review feedback. The evidence (disrupted Purkinje neuron
# synaptic formation in Elavl3-/- mice) is an indirect phenotypic
# consequence of losing an RNA-binding regulator, not direct molecular
# evidence that ELAVL3 itself regulates synaptic plasticity. Using a proxy
# GO term because the ideal "regulation of neuronal excitability" term is
# absent is not sound curation practice; moved to proposed_new_terms below.
core_functions:
- description: Binding to AU-rich and GU-rich elements in mRNA 3'-UTRs to stabilize
    target transcripts and regulate alternative splicing events in neurons
  molecular_function:
    id: GO:0035925
    label: mRNA 3'-UTR AU-rich region binding
  directly_involved_in:
  - id: GO:0030182
    label: neuron differentiation
  - id: GO:0007399
    label: nervous system development
  - id: GO:0010608
    label: post-transcriptional regulation of gene expression
  locations:
  - id: GO:0005634
    label: nucleus
  - id: GO:0005737
    label: cytoplasm
  anatomical_locations:
  - id: UBERON:0002129
    label: cerebellar cortex
  - id: UBERON:0002421
    label: hippocampal formation
  substrates:
  - id: UniProtKB:P15692
    label: VEGFA mRNA
  - id: UniProtKB:P01106
    label: MYC mRNA
  - id: UniProtKB:P17677
    label: GAP43 mRNA
  supported_by:
  - reference_id: PMID:10710437
    supporting_text: With this assay, I demonstrate that HuC and HuD bind to the VEGF
      3'-UTR regulatory segment (VRS) and to the c- myc 3'-UTR in a specific and concentration-dependent
      pattern, with both proteins showing a greater affinity for the VRS
  - reference_id: file:human/ELAVL3/ELAVL3-deep-research-perplexity-lite.md
    supporting_text: ELAVL3 binds preferentially to GU-rich and AU-rich sequences
      in intronic regions and 3'-untranslated regions (3'-UTRs) of target pre-mRNAs.
      This binding regulates alternative splicing, mRNA stability, and transcript
      abundance
  - reference_id: UniProtKB:Q14576
    supporting_text: RNA-binding protein that binds to AU-rich element (ARE) sequences
      of target mRNAs, including VEGF mRNA. Plays a role in the stabilization of GAP43
      mRNA and in spatial learning
  in_complex:
    id: GO:1990904
    label: ribonucleoprotein complex
- description: Regulating neuronal alternative splicing and alternative polyadenylation/3'-UTR
    length choice of target transcripts, including AnkG/ANK3 exon 34 and a broader
    program of glutamate-regulating and excitability-related transcripts
  molecular_function:
    id: GO:0003729
    label: mRNA binding
  directly_involved_in:
  - id: GO:0000380
    label: alternative mRNA splicing, via spliceosome
  - id: GO:0110104
    label: mRNA alternative polyadenylation
  - id: GO:0010608
    label: post-transcriptional regulation of gene expression
  locations:
  - id: GO:0005634
    label: nucleus
  - id: GO:0005737
    label: cytoplasm
  anatomical_locations:
  - id: UBERON:0002129
    label: cerebellar cortex
  - id: UBERON:0001870
    label: frontal cortex
  supported_by:
  - reference_id: PMID:37697079
    supporting_text: Elavl3 regulates the embryonic-specific inclusion of vertebrate-specific
      exon 34 in the AnkG transcript.
  - reference_id: PMID:37697079
    supporting_text: High-throughput sequencing analysis of alternative splicing in
      the cerebellum of Elavl3−/− mice highlighted the convergence of targeted transcripts
      on glutamate levels and neuronal excitability
  - reference_id: PMID:37862432
    supporting_text: the neuron-enriched ELAVL family of genes (ELAVL2, ELAVL3, and
      ELAVL4) can increase (i) 3'UTR length, (ii) dsRNA load, and (iii) activation
      of dsRNA-sensing PRRs such as MDA5, PKR, and TLR3
  - reference_id: file:human/ELAVL3/ELAVL3-deep-research-falcon.md
    supporting_text: ELAVL3 has a documented role in alternative splicing; all three
      RRMs plus the hinge region contribute to HuC-dependent splice regulation, and
      ELAVL3 loss alters neuronal splicing programs linked to excitability.
  in_complex:
    id: GO:1990904
    label: ribonucleoprotein complex
- description: Adapting AU-rich mRNA transcripts to post-transcriptional regulatory
    complexes to control neuronal gene expression programs
  molecular_function:
    id: GO:0140517
    label: protein-RNA adaptor activity
  directly_involved_in:
  - id: GO:0030182
    label: neuron differentiation
  - id: GO:0007399
    label: nervous system development
  - id: GO:0010608
    label: post-transcriptional regulation of gene expression
  locations:
  - id: GO:0005634
    label: nucleus
  - id: GO:0005737
    label: cytoplasm
  anatomical_locations:
  - id: UBERON:0002129
    label: cerebellar cortex
  - id: UBERON:0002421
    label: hippocampal formation
  supported_by:
  - reference_id: file:human/ELAVL3/ELAVL3-deep-research-perplexity-lite.md
    supporting_text: ELAVL3 is involved in the development and maintenance of neurons.
      ELAVL3 binds over 1,100 transcripts in neuroendocrine cancer cell lines, with
      enrichment for genes involved in neuron projection development and synapse organization
  - reference_id: UniProtKB:Q14576
    supporting_text: May be involved in neuronal differentiation and maintenance.
      Plays a role in the stabilization of GAP43 mRNA
  in_complex:
    id: GO:1990904
    label: ribonucleoprotein complex
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms.
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara.
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods.
  findings: []
- id: PMID:10710437
  title: RNA-binding analyses of HuC and HuD with the VEGF and c-myc 3'-untranslated
    regions using a novel ELISA-based assay.
  findings: []
- id: PMID:36950384
  title: Protein interaction studies in human induced neurons indicate convergent
    biology underlying autism spectrum disorders.
  findings: []
- id: PMID:37207277
  title: Using brain cell-type-specific protein interactomes to interpret neurodevelopmental
    genetic signals in schizophrenia.
  findings: []
- id: PMID:37697079
  title: The molecular genetics of nELAVL in brain development and disease.
  findings:
  - statement: ELAVL3 is the only nELAVL expressed in Purkinje neurons; Elavl3 knockout
      mice develop progressive cerebellar ataxia with disrupted Purkinje synaptic
      formation, swollen axons, and neuronal transport deficits, and Elavl3+/- and
      -/- mice show seizure activity.
    supporting_text: As Elavl3−/− mice aged, progressive severe cerebellar ataxia
      was observed. This ataxia caused an abnormal step cycle, tremor and over time,
      impaired postural reflexes. At the cellular level, Purkinje neurons had disrupted
      synaptic formation, swollen axons, and overall deficits in neuronal transport,
      highlighting the requirement for Elavl3 activity in these neurons
    reference_section_type: RESULTS
  - statement: ELAVL3 regulates alternative splicing of neuronal transcripts converging
      on glutamate regulation and excitability, including embryonic-specific inclusion
      of AnkG exon 34; ELAVL3 also drives 3'-UTR lengthening via distal poly(A) site
      usage during inhibitory neuron differentiation.
    supporting_text: High-throughput sequencing analysis of alternative splicing in
      the cerebellum of Elavl3−/− mice highlighted the convergence of targeted transcripts
      on glutamate levels and neuronal excitability—linking RNA regulation to the
      seizure activity observed in Elavl3−/− mice
    reference_section_type: RESULTS
  - statement: All four ELAVL proteins share three RNA recognition motifs (RRMs)
      with a hinge region; RRM1 and RRM2 directly bind AU-rich elements in 3'-UTRs,
      while RRM3 supports transcript stability via poly(A)-associated mechanisms.
    supporting_text: Binding to RNA targets is facilitated by the RRM1 and RRM2 domains
      preferentially recognising AU-rich elements in the 3ʹUTR of transcripts
    reference_section_type: LITERATURE_REVIEW
- id: PMID:37862432
  title: Long 3'UTRs predispose neurons to inflammation by promoting immunostimulatory
    double-stranded RNA formation.
  findings:
  - statement: The neuron-enriched ELAVL family (ELAVL2, ELAVL3, ELAVL4) collectively
      drives 3'-UTR lengthening in human neurons, which in turn raises dsRNA load
      and tonically activates dsRNA-sensing PRRs (MDA5, PKR, TLR3).
    supporting_text: the neuron-enriched ELAVL family of genes (ELAVL2, ELAVL3, and
      ELAVL4) can increase (i) 3'UTR length, (ii) dsRNA load, and (iii) activation
      of dsRNA-sensing PRRs such as MDA5, PKR, and TLR3
    reference_section_type: ABSTRACT
- id: PMID:32954318
  title: High-resolution epitope mapping of anti-Hu and anti-Yo autoimmunity by programmable
    phage display.
  findings:
  - statement: ELAVL3/HuC is one of the neuronal ELAVL (nELAVL) proteins targeted
      by anti-Hu paraneoplastic autoantibodies; the dominant immunodominant epitope
      maps to a 17-residue motif in the hinge region between RRM2 and RRM3 shared
      across ELAVL2/3/4, with most enriched peptides (>80%) attributed to ELAVL4.
    supporting_text: A majority (>90%) of the significantly enriched nELAVL peptides
      converged upon on a 17-residue sequence at AA positions 276–294 of ELAVL4, a
      sequence which is also common to variants of ELAVL2 and ELAVL3
    reference_section_type: RESULTS
- id: PMID:40000387
  title: ELAV/Hu RNA-binding protein family - key regulators in neurological disorders,
    cancer, and other diseases.
  findings:
  - statement: ELAVL3 is restricted to the nervous system, essential for cerebellar
      function, and involved in neuronal differentiation and excitability; ELAVL3
      dysregulation is associated with epilepsy.
    supporting_text: Both Elavl3 and Elavl4 are restricted to the nervous system and
      are involved in neuronal differentiation and excitability. Elavl3 is essential
      for cerebellar function and has been associated with epilepsy
    reference_section_type: ABSTRACT
- id: file:human/ELAVL3/ELAVL3-deep-research-falcon.md
  title: 'Falcon (Edison Scientific Literature) deep research report: ELAVL3 (HuC)
    functional annotation'
  findings:
  - statement: ELAVL3 functions as a post-transcriptional regulator that uses three
      RRMs plus a hinge region to bind AU-/U-rich elements in 3'-UTRs, with RRM3 contributing
      poly(A)-tail binding; functions span splicing, APA/3'-UTR length, mRNA stability,
      and translation. ELAVL3 is predominantly cytoplasmic with nucleocytoplasmic
      shuttling.
    supporting_text: ELAVL3 functions primarily as a post-transcriptional regulator
      that stabilizes target transcripts, in part by binding AU-rich elements and
      influencing poly(A)-tail-associated protection; ELAVL proteins can multimerize
      on RNA and oppose destabilizing factors.
    reference_section_type: OTHER
  - statement: ELAVL3 has a documented role in alternative splicing in which all three
      RRMs plus the hinge region contribute to HuC-dependent splice regulation; ELAVL3
      loss alters neuronal splicing programs linked to excitability.
    supporting_text: ELAVL3 has a documented role in alternative splicing; all three
      RRMs plus the hinge region contribute to HuC-dependent splice regulation, and
      ELAVL3 loss alters neuronal splicing programs linked to excitability.
    reference_section_type: OTHER
  - statement: ELAVL3 participates in alternative polyadenylation control of neuronal
      3'-UTR length; ELAVL3 depletion shifts poly(A) usage toward proximal sites.
    supporting_text: ELAVL3 participates in regulation of alternative polyadenylation
      and 3′UTR length in neurons. ELAVL3 depletion shifts usage toward proximal poly(A)
      sites, whereas neuronal ELAVL proteins promote longer neuronal 3′UTRs.
    reference_section_type: OTHER