id: Q9PWC2
gene_symbol: mitfa
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:7955
  label: Danio rerio
description: >-
  mitfa (nacre) encodes microphthalmia-associated transcription factor a, a basic
  helix-loop-helix leucine zipper (bHLH-LZ) transcription factor of the MiT/TFE family and
  one of two zebrafish co-orthologs of human MITF that arose in the teleost genome
  duplication (the other is mitfb). The 412-residue protein carries the MiT/TFE N-terminal
  region, the bHLH-LZ DNA-binding and dimerization domain and the MiT/TFE C-terminal region,
  and resembles the melanocyte-specific M isoform of mammalian MITF. mitfa is expressed in
  all embryonic melanogenic cells, including neural crest melanoblasts and the retinal
  pigment epithelium (RPE), and is the master transcriptional regulator of neural
  crest-derived melanophore (melanocyte) development: nacre null mutants lack melanophores
  throughout life, have supernumerary iridophores, and misexpression of mitfa induces ectopic
  melanized cells. Temperature-sensitive alleles show that mitfa is needed at several steps of
  melanophore differentiation (dct onset, progression to pigmentation and maintenance of
  dendritic form) but not to establish melanocyte stem cells. mitfa acts in parallel with
  TFAP2 factors and represses tfec in melanoblasts, biasing multipotent pigment progenitors
  away from the iridophore fate. mitfa is not required for RPE development, where it is
  redundant with mitfb and tfec; with tfec it is required in cranial neural crest cells for
  choroid (optic) fissure closure, and with mitfb and tfec it contributes to xanthophore
  development.
existing_annotations:
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  supporting_entities:
  - MGI:MGI:103270
  - MGI:MGI:104554
  - MGI:MGI:98511
  - PANTHER:PTN005248237
  - RGD:3846
  - UniProtKB:O75030
  review:
    summary: >-
      Phylogenetic inference of sequence-specific cis-regulatory DNA binding from the MiT/TFE
      node (PTN005248237), grounded in mammalian MITF/TFE3/TFEB. mitfa retains the full bHLH-LZ
      domain, and mitfa missense substitutions in the DNA-binding domain abolish or impair its
      activity in vivo.
    action: ACCEPT
    reason: >-
      mitfa is inside the MiT/TFE clade, carries an intact basic region, and there is no
      evidence of loss of DNA binding; a DNA-binding-domain missense allele identical to mouse
      alleles is dominant negative, consistent with DNA binding being central to its function.
    supported_by:
    - reference_id: PMID:40123122
      supporting_text: Harboring a missense substitution in the DNA-binding domain identical to previously isolated alleles of mouse
    - reference_id: PMID:21146516
      supporting_text: asparagine to tyrosine amino acid substitution in the DNA-binding domain
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  supporting_entities:
  - FB:FBgn0263112
  - MGI:MGI:103270
  - MGI:MGI:104554
  - PANTHER:PTN005248237
  - RGD:3846
  - SGD:S000000199
  - UniProtKB:O14948
  - UniProtKB:O75030
  - UniProtKB:P19532
  - ZFIN:ZDB-GENE-010919-1
  - ZFIN:ZDB-GENE-010919-2
  - ZFIN:ZDB-GENE-990910-11
  review:
    summary: >-
      Core molecular function of mitfa, inferred from the MiT/TFE family node. mitfa itself
      (ZFIN:ZDB-GENE-990910-11) is among the descendant evidences, reflecting its own IDA
      annotation from PMID:11543618; this is expected, not circular.
    action: ACCEPT
    reason: >-
      Transcription factor activity is the ancestral and retained function of the MiT/TFE
      family and is directly supported for mitfa.
    supported_by:
    - reference_id: PMID:10433906
      supporting_text: nac(w2) is a mutation in a zebrafish gene encoding a basic helix-loop-helix/leucine zipper transcription factor related to microphthalmia (Mitf)
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: IDA
  original_reference_id: PMID:11543618
  qualifier: enables
  review:
    summary: >-
      Direct assay from Lister et al. 2001 (abstract-only in cache), which characterized both
      zebrafish mitf proteins. The abstract supports the conserved melanogenic activity of the
      paralogs; the transcriptional assay details are in the full text that the curator read.
    action: ACCEPT
    reason: >-
      Consistent with the family function, the IBA, and in vivo evidence that mitfa drives
      melanogenic gene expression (e.g. dct) and ectopic melanization. Deferring to the curator
      for the assay details.
    supported_by:
    - reference_id: PMID:11543618
      supporting_text: These data suggest that mitfa and mitfb together may recapitulate the expression and functions of a single ancestral Mitf gene
    - reference_id: PMID:21146516
      supporting_text: mitfa is required at several stages of melanocyte differentiation, including for expression of the early melanoblast marker dct
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  supporting_entities:
  - MGI:MGI:104554
  - MGI:MGI:98511
  - PANTHER:PTN005248237
  - SGD:S000000199
  - UniProtKB:O14948
  - UniProtKB:O75030
  - UniProtKB:P19484
  - UniProtKB:P19532
  review:
    summary: >-
      Nuclear site of action inferred for the MiT/TFE family; appropriate for a
      sequence-specific transcription factor.
    action: ACCEPT
    reason: A DNA-binding transcription factor acts in the nucleus; no evidence of divergence.
    supported_by:
    - reference_id: file:DANRE/mitfa/mitfa-deep-research-falcon.md
      supporting_text: Mitfa performs its primary function in the **nucleus**, where it regulates transcription at E-box-like elements.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  supporting_entities:
  - UniProtKB-SubCell:SL-0191
  - UniRule:UR000414447
  review:
    summary: Automated nuclear localization, consistent with the IBA and TF function.
    action: ACCEPT
    reason: Consistent with the IBA nucleus annotation and the transcription factor activity.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IC
  original_reference_id: PMID:11543618
  qualifier: located_in
  supporting_entities:
  - GO:0000981
  review:
    summary: >-
      Curator inference of nucleoplasmic location from the directly assayed transcription
      factor activity.
    action: ACCEPT
    reason: A reasonable IC from GO:0000981; consistent with the nuclear annotations.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  supporting_entities:
  - UniProtKB-SubCell:SL-0086
  review:
    summary: >-
      Family-level (ARBA) subcellular-location mapping. MiT/TFE proteins can be retained in
      the cytoplasm under some conditions, but no zebrafish mitfa-specific localization data
      were found.
    action: KEEP_AS_NON_CORE
    reason: >-
      Plausible for a MiT/TFE factor whose activity is regulated by nuclear entry, but the
      active pool is nuclear and there is no mitfa-specific evidence; retained as non-core.
- term:
    id: GO:0006351
    label: DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:11543618
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      Companion BP annotation to the IDA for transcription factor activity. A sequence-specific
      transcription factor regulates RNA polymerase II transcription rather than executing
      DNA-templated transcription itself.
    action: MODIFY
    reason: >-
      The essence (mitfa controls transcription) is sound, but the regulatory term matches the
      molecular function better; the same change is made for mitfb so the pair stays
      consistent.
    proposed_replacement_terms:
    - id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    supported_by:
    - reference_id: PMID:10433906
      supporting_text: nac(w2) is a mutation in a zebrafish gene encoding a basic helix-loop-helix/leucine zipper transcription factor related to microphthalmia (Mitf)
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  supporting_entities:
  - InterPro:IPR021802
  review:
    summary: InterPro2GO mapping from the MiT/TFE C-terminal domain; broad but correct.
    action: ACCEPT
    reason: Correct general parent of the RNA polymerase II-specific regulation term.
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  supporting_entities:
  - FB:FBgn0263112
  - MGI:MGI:103270
  - MGI:MGI:104554
  - MGI:MGI:98511
  - PANTHER:PTN005248237
  - RGD:3846
  - SGD:S000000199
  - UniProtKB:O14948
  - UniProtKB:O75030
  - UniProtKB:P19484
  - UniProtKB:P19532
  - WB:WBGene00020930
  review:
    summary: Family-level process for a RNA polymerase II transcription factor.
    action: ACCEPT
    reason: Correct and at an appropriate level of generality for the MF.
- term:
    id: GO:0007623
    label: circadian rhythm
  evidence_type: IDA
  original_reference_id: PMID:26278158
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      Annotation from a paper describing lypc, a dark-inducible Ly6 gene in pigment cells.
      The cached abstract does not mention mitfa; the IDA probably reflects diurnal variation
      of mitfa expression measured in the full text, which is not available here.
    action: UNDECIDED
    reason: >-
      Cannot verify the evidence (abstract only, mitfa not mentioned). Rhythmic expression
      alone would not show that mitfa acts in the circadian rhythm process, but without the
      full text this is left undecided rather than removed.
    supported_by:
    - reference_id: PMID:26278158
      supporting_text: the expression of lypc displays a clear rhythmic pattern, and dark exposure apparently stimulated its expression
- term:
    id: GO:0030318
    label: melanocyte differentiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  supporting_entities:
  - PANTHER:PTN000000863
  - ZFIN:ZDB-GENE-010919-1
  - ZFIN:ZDB-GENE-990910-11
  review:
    summary: >-
      Phylogenetic inference placed at the MITF node (PTN000000863), seeded by the zebrafish
      mitfa and mitfb experimental annotations. mitfa's own experimental annotation is a
      legitimate descendant evidence.
    action: ACCEPT
    reason: The core biological process of mitfa, strongly supported by mutant evidence.
    supported_by:
    - reference_id: PMID:10433906
      supporting_text: Homozygous nacre (nac(w2)) mutants lack melanophores throughout development but have increased numbers of iridophores.
- term:
    id: GO:0030318
    label: melanocyte differentiation
  evidence_type: IGI
  original_reference_id: PMID:20862309
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-MRPHLNO-060927-2
  - ZFIN:ZDB-MRPHLNO-101013-2
  review:
    summary: >-
      Genetic interaction with tfap2a/tfap2e knockdown: forced mitfa expression partially
      restores melanophore differentiation in Tfap2-deficient embryos.
    action: ACCEPT
    reason: Consistent with mitfa acting in melanocyte differentiation in parallel with TFAP2.
    supported_by:
    - reference_id: PMID:20862309
      supporting_text: forcing expression of mitfa in tfap2a/e doubly-deficient embryos partially restores melanophore differentiation
- term:
    id: GO:0030318
    label: melanocyte differentiation
  evidence_type: IGI
  original_reference_id: PMID:28249010
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENE-011212-6
  review:
    summary: Genetic interaction between mitfa and tfap2a in melanocyte development.
    action: ACCEPT
    reason: Full text shows a synergistic mitfa;tfap2a interaction affecting melanocytes.
    supported_by:
    - reference_id: PMID:28249010
      supporting_text: we observed a genetic interaction between mitfa and tfap2a affecting melanocyte development in zebrafish
- term:
    id: GO:0030318
    label: melanocyte differentiation
  evidence_type: IGI
  original_reference_id: PMID:28249010
  qualifier: acts_upstream_of_or_within_positive_effect
  supporting_entities:
  - ZFIN:ZDB-GENE-011212-6
  review:
    summary: Same genetic interaction as above, recorded with a positive-effect qualifier.
    action: ACCEPT
    reason: Supported by the mitfa;tfap2a double-mutant analysis.
    supported_by:
    - reference_id: PMID:28249010
      supporting_text: tfap2a+/- embryos in both mitfa mutant backgrounds had significantly fewer melanocytes in the ventral stripe
- term:
    id: GO:0030318
    label: melanocyte differentiation
  evidence_type: IMP
  original_reference_id: PMID:10433906
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-990423-18
  review:
    summary: >-
      The founding nacre paper: mitfa null mutants lack neural crest melanophores; the
      defect is cell autonomous and rescued by wild-type mitfa.
    action: ACCEPT
    reason: Definitive loss-of-function and rescue evidence for the core process.
    supported_by:
    - reference_id: PMID:10433906
      supporting_text: Transient expression of the wild-type nacre gene restored melanophore development in nacre(-/-) embryos.
- term:
    id: GO:0030318
    label: melanocyte differentiation
  evidence_type: IMP
  original_reference_id: PMID:11543618
  qualifier: acts_upstream_of_or_within
  review:
    summary: nacre/mitfa mutants perturb neural crest melanocytes (Lister et al. 2001).
    action: ACCEPT
    reason: Consistent with the nacre phenotype.
    supported_by:
    - reference_id: PMID:11543618
      supporting_text: Mutations in the zebrafish nacre/mitfa gene, expressed in all embryonic melanogenic cells, perturb only neural crest melanocytes
- term:
    id: GO:0030318
    label: melanocyte differentiation
  evidence_type: IMP
  original_reference_id: PMID:15300437
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-MRPHLNO-050201-1
  review:
    summary: >-
      mitfa morpholino knockdown delays melanoblast development; used as a tool to reveal a
      kit requirement.
    action: ACCEPT
    reason: The morphant delay of melanoblast development is consistent with mitfa's role.
    supported_by:
    - reference_id: PMID:15300437
      supporting_text: When melanoblast development in zebrafish embryos is delayed by injecting morpholinos targeted to the mitfa gene
- term:
    id: GO:0030318
    label: melanocyte differentiation
  evidence_type: IMP
  original_reference_id: PMID:20862309
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-070315-1
  review:
    summary: mitfa mutant genotype used in the Tfap2 melanophore study.
    action: ACCEPT
    reason: Consistent with the established requirement for mitfa in melanophore differentiation.
    supported_by:
    - reference_id: PMID:20862309
      supporting_text: Tfap2 activity, mediated redundantly by Tfap2a and Tfap2e, promotes melanophore differentiation in parallel with Mitf
- term:
    id: GO:0030318
    label: melanocyte differentiation
  evidence_type: IMP
  original_reference_id: PMID:21146516
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-100727-8
  review:
    summary: Hypomorphic and temperature-sensitive mitfa alleles define multiple requirements.
    action: ACCEPT
    reason: Strong allelic-series evidence for mitfa acting within melanocyte differentiation.
    supported_by:
    - reference_id: PMID:21146516
      supporting_text: mitfa is required at several stages of melanocyte differentiation, including for expression of the early melanoblast marker dct
- term:
    id: GO:0030318
    label: melanocyte differentiation
  evidence_type: IMP
  original_reference_id: PMID:21146516
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-110330-3
  review:
    summary: Second genotype from the same allelic series (temperature-sensitive allele).
    action: ACCEPT
    reason: Same evidence as above.
    supported_by:
    - reference_id: PMID:21146516
      supporting_text: again for maintenance of dendritic form following differentiation
- term:
    id: GO:0030318
    label: melanocyte differentiation
  evidence_type: IMP
  original_reference_id: PMID:23364329
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-MRPHLNO-130429-1
  review:
    summary: >-
      Mitfa morpholino depletes larval melanophores and prematurely activates embryonic
      melanophore progenitors.
    action: ACCEPT
    reason: Consistent with mitfa's requirement for melanophore differentiation.
    supported_by:
    - reference_id: PMID:23364329
      supporting_text: Upon depletion of larval melanophores by morpholino knockdown of Mitfa, the embryonic MPs are prematurely activated
- term:
    id: GO:0030318
    label: melanocyte differentiation
  evidence_type: IMP
  original_reference_id: PMID:25535837
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-100727-8
  review:
    summary: nacre/mitfa mutants lacking melanophores used in adult stripe-pattern analysis.
    action: ACCEPT
    reason: The paper re-uses the melanophore-less nacre phenotype; consistent with the core role.
    supported_by:
    - reference_id: PMID:25535837
      supporting_text: in mutants for nacre/mitfA melanophores are missing
- term:
    id: GO:0030318
    label: melanocyte differentiation
  evidence_type: IMP
  original_reference_id: PMID:28249010
  qualifier: acts_upstream_of_or_within_positive_effect
  supporting_entities:
  - ZFIN:ZDB-GENO-110330-4
  review:
    summary: mitfa allele combinations (w2/z25) with reduced melanocytes.
    action: ACCEPT
    reason: Consistent with mitfa promoting melanocyte differentiation.
    supported_by:
    - reference_id: PMID:28249010
      supporting_text: nor did it improve the quality or pigmentation of melanocytes in mitfaz25/z25 and mitfaw2/z25 mutants
- term:
    id: GO:0043473
    label: pigmentation
  evidence_type: IGI
  original_reference_id: PMID:28249010
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENE-011212-6
  review:
    summary: Broad pigmentation term from the mitfa;tfap2a interaction.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but general; the specific process (melanocyte differentiation) is already
      annotated from the same paper.
- term:
    id: GO:0043473
    label: pigmentation
  evidence_type: IMP
  original_reference_id: PMID:25214630
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-100727-8
  review:
    summary: >-
      Xanthophore time-lapse study of adult stripe formation (abstract only); the nacre
      genotype was presumably used to remove melanophores.
    action: KEEP_AS_NON_CORE
    reason: >-
      Broad but correct for mitfa (loss of melanophores alters the adult pigment pattern);
      deferring to the curator on the full-text details.
    supported_by:
    - reference_id: PMID:25214630
      supporting_text: Thus, xanthophores, attracted by iridophores and repelling melanophores, sharpen and color the pattern.
- term:
    id: GO:0045636
    label: positive regulation of melanocyte differentiation
  evidence_type: IMP
  original_reference_id: PMID:33439865
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-100727-8
  review:
    summary: >-
      Petratou et al. show that Mitfa represses tfec in melanoblasts, contributing to the
      melanocyte versus iridophore fate choice.
    action: ACCEPT
    reason: >-
      mitfa as master regulator promotes melanocyte fate; positive regulation of melanocyte
      differentiation is an appropriate description for a lineage-determining TF.
    supported_by:
    - reference_id: PMID:33439865
      supporting_text: We show that Mitfa represses tfec expression, revealing a likely mechanism contributing to the decision between melanocyte and iridophore fate.
- term:
    id: GO:0046983
    label: protein dimerization activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  supporting_entities:
  - InterPro:IPR011598
  - InterPro:IPR036638
  review:
    summary: >-
      InterPro2GO mapping from the HLH domain. bHLH-LZ factors bind DNA as dimers, so the
      mapping is correct, but it describes part of the TF mechanism.
    action: KEEP_AS_NON_CORE
    reason: Correct domain-based inference; subsidiary to the transcription factor activity.
- term:
    id: GO:0061386
    label: closure of optic fissure
  evidence_type: IGI
  original_reference_id: PMID:32541011
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-211027-12
  review:
    summary: >-
      mitfa;tfec double mutants have colobomas; Mitf activity is needed in cranial neural
      crest cells for choroid fissure closure. mitfa single mutants close the fissure normally.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real but redundant (with tfec) role in eye morphogenesis; not the primary function of
      mitfa.
    supported_by:
    - reference_id: PMID:32541011
      supporting_text: mitfa;tfec mutants possess severe colobomas and our data demonstrate that Mitf activity is required within cranial neural crest cells (cNCCs) during CF closure
- term:
    id: GO:0071228
    label: cellular response to tumor cell
  evidence_type: IMP
  original_reference_id: PMID:35929478
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-240110-1
  review:
    summary: >-
      Travnickova-style conditional melanoma model in which a temperature-sensitive mitfa
      splicing allele switches MITF activity in the tumour cells, driving tumour regression and
      recurrence. The full text was read.
    action: REMOVE
    reason: >-
      GO:0071228 is defined as a change in a cell as a result of a stimulus from a tumor cell.
      In this paper mitfa is the oncogenic driver acting within the melanoma cells themselves;
      nothing is shown about mitfa mediating a response of cells to tumour cells. The
      experiment is valid, but the term does not describe it.
    supported_by:
    - reference_id: PMID:35929478
      supporting_text: At the lower permissive temperature, MITF activity is on and promotes tumourigenesis
- term:
    id: GO:0050936
    label: xanthophore differentiation
  evidence_type: IGI
  original_reference_id: PMID:37823232
  review:
    summary: >-
      NEW (proposed). mitfa contributes, redundantly with mitfb and tfec, to xanthophore
      development. mitfa;mitfb double nulls have fewer xanthophores than mitfa single mutants
      in two independent studies, and a dominant-negative DNA-binding-domain mitfa allele
      eliminates xanthophores through interference with Tfec.
    action: NEW
    reason: >-
      Participation: MiT factors directly activate xanthophore pigment genes (gch2) in the
      lineage, so mitfa does part of the work as a transcription factor, not merely as a
      prerequisite. Proposed equally for mitfb, since the evidence is from double mutants and
      applies to both copies.
    supported_by:
    - reference_id: PMID:37823232
      supporting_text: the results suggest that in zebrafish xanthophore development may be partially dependent on Mitf function
    - reference_id: PMID:40123122
      supporting_text: Our findings point to collaborative roles for Mitfa and Tfec in promoting chromatophore development, particularly in xanthophore lineages
    - reference_id: file:DANRE/mitfa/mitfa-deep-research-falcon.md
      supporting_text: Genetic evidence also supports partial redundancy with **Tfec**.
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: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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:DANRE/mitfa/mitfa-deep-research-falcon.md
  title: Deep research report (Falcon) for zebrafish mitfa
  findings: []
- id: PMID:10433906
  title: nacre encodes a zebrafish microphthalmia-related protein that regulates neural-crest-derived
    pigment cell fate.
  findings:
  - statement: mitfa null mutants lack neural crest melanophores but have a normal RPE.
    supporting_text: The non-crest-derived retinal pigment epithelium is normal
- id: PMID:11543618
  title: 'Duplicate mitf genes in zebrafish: complementary expression and conservation
    of melanogenic potential.'
  findings:
  - statement: mitfb is coexpressed with mitfa in the RPE but not in neural crest melanoblasts.
    supporting_text: mitfb is coexpressed with mitfa in the RPE at an appropriate time to compensate for loss of mitfa function in the nacre mutant but is not expressed in neural crest melanoblasts
- id: PMID:12019239
  title: Subfunctionalization of duplicate mitf genes associated with differential degeneration
    of alternative exons in fish.
  findings:
  - statement: Each fish Mitf protein corresponds to one tetrapod MITF isoform.
    supporting_text: Fish proteins MITF-m and MITF-b correspond at both the structural and the expression levels to one particular bird/mammalian MITF isoform.
- id: PMID:15300437
  title: A requirement for kit in embryonic zebrafish melanocyte differentiation is
    revealed by melanoblast delay.
  findings: []
- id: PMID:20862309
  title: Differentiation of zebrafish melanophores depends on transcription factors
    AP2 alpha and AP2 epsilon.
  findings: []
- id: PMID:21146516
  title: mitfa is required at multiple stages of melanocyte differentiation but not
    to establish the melanocyte stem cell.
  findings: []
- id: PMID:23139843
  title: Otx but not Mitf transcription factors are required for zebrafish retinal pigment
    epithelium development.
  findings:
  - statement: mitfa, mitfb and double mitf mutants have normal RPE; misexpressed mitfa induces retinal pigmentation.
    supporting_text: the loss of Mitf activity in mitfa, mitfb, or double mitf mutant zebrafish had no effect on RPE pigmentation or development
- id: PMID:23364329
  title: 'On the embryonic origin of adult melanophores: the role of ErbB and Kit
    signalling in establishing melanophore stem cells in zebrafish.'
  findings: []
- id: PMID:25214630
  title: Local reorganization of xanthophores fine-tunes and colors the striped pattern
    of zebrafish.
  findings: []
- id: PMID:25535837
  title: Gap junctions composed of connexins 41.8 and 39.4 are essential for colour
    pattern formation in zebrafish.
  findings: []
- id: PMID:26278158
  title: Identification and expression of lypc, a novel dark-inducible member of Ly6
    superfamily in zebrafish Danio rerio.
  findings: []
- id: PMID:28249010
  title: TFAP2 paralogs regulate melanocyte differentiation in parallel with MITF.
  findings: []
- id: PMID:32541011
  title: Mitf-family transcription factor function is required within cranial neural
    crest cells to promote choroid fissure closure.
  findings: []
- id: PMID:33439865
  title: The MITF paralog tfec is required in neural crest development for fate specification
    of the iridophore lineage from a multipotent pigment cell progenitor.
  findings: []
- id: PMID:35929478
  title: Fate mapping melanoma persister cells through regression and into recurrent
    disease in adult zebrafish.
  findings: []
- id: PMID:37823232
  title: A gene regulatory network combining Pax3/7, Sox10 and Mitf generates diverse
    pigment cell types in medaka and zebrafish.
  findings:
  - statement: Zebrafish mitfa;mitfb double mutants have fewer trunk xanthophores than mitfa single mutants.
    supporting_text: Compared with a single mitfa mutant, mitfa−/−; mitfb−/− double mutants showed a slightly more severe reduction of xanthophores, with fewer fluorescent xanthophores on the trunk
- id: PMID:40123122
  title: Dominant Negative Mitf Allele Impacts Melanophore and Xanthophore Development
    and Reveals Collaborative Interactions With Tfec in Zebrafish Chromatophore Lineages.
  findings:
  - statement: A dominant-negative mitfa DNA-binding-domain allele removes melanophores and xanthophores.
    supporting_text: Here we identify a new allele of the zebrafish Mitf gene, mitfa, that results in a complete absence of not only melanophores but also yellow-orange xanthophores.
- id: PMID:42663426
  title: MIT/TFE family transcription factors, Mitf and Tfec, redundantly promote pigment
    cell differentiation and retinal epithelium pigmentation in teleosts.
  findings:
  - statement: mitfa, mitfb and tfec are jointly required for RPE pigmentation (triple null).
    supporting_text: simultaneous null mutations in all three genes cause a complete loss of all four chromatophore types and lead to defective pigmentation of the retinal pigmented epithelium (RPE)
core_functions:
- description: >-
    mitfa is the master bHLH-LZ transcription factor of the zebrafish neural crest melanophore
    lineage. It binds cis-regulatory DNA in the nucleus and activates melanogenic genes
    such as dct, and it is required cell autonomously at several steps of melanophore
    differentiation.
  molecular_function:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  directly_involved_in:
  - id: GO:0030318
    label: melanocyte differentiation
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:10433906
    supporting_text: Homozygous nacre (nac(w2)) mutants lack melanophores throughout development but have increased numbers of iridophores.
  - reference_id: PMID:21146516
    supporting_text: mitfa is required at several stages of melanocyte differentiation, including for expression of the early melanoblast marker dct
suggested_questions:
- question: >-
    Is mitfa's contribution to xanthophore development direct (cell-autonomous activation of
    pteridine-pathway genes such as gch2 in xanthoblasts, as shown in medaka) or indirect
    through tfec cross-regulation?
- question: >-
    Does the IDA circadian rhythm annotation from PMID:26278158 rest on anything beyond
    diurnal variation of mitfa transcript levels?
- question: >-
    Since mitfa, mitfb and tfec are jointly required for RPE pigmentation (PMID:42663426), which
    of the three normally carries most of the RPE melanogenic transcription in wild type?
suggested_experiments:
- hypothesis: mitfa directly regulates xanthophore pigment-synthesis genes in zebrafish.
  description: >-
    Lineage-restricted CUT&RUN or ChIP-seq for tagged Mitfa in sorted xanthoblasts, combined
    with RNA-seq of mitfa;mitfb double mutant xanthophores, to test direct binding at gch2 and
    other pteridine-pathway loci.
  experiment_type: genomics