id: O57341 gene_symbol: fgf8a product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:7955 label: Danio rerio description: fgf8a is the zebrafish orthologue of vertebrate FGF8 and one of two co-orthologues (with fgf8b) retained from the teleost-specific genome duplication; it is the gene mutated in acerebellar (ace). It encodes a secreted fibroblast growth factor of the FGF8/17/18 (FgfD) subfamily, with an N-terminal signal peptide and the FGF beta-trefoil core, that acts as an extracellular ligand for FGF receptor tyrosine kinases and activates Ras/MAPK signalling. Its spread through tissue is limited by endocytosis and lysosomal degradation in receiving cells, which shapes a signalling gradient. fgf8a is expressed from the blastula onward, in a dorsoventral gradient during gastrulation and later at the midbrain-hindbrain boundary, dorsal diencephalon, telencephalon, somites, tailbud, heart precursors, pharyngeal region, otic region and pectoral fin bud. It is required for the midbrain-hindbrain boundary (isthmic) organizer and cerebellum, for induction of myocardial precursors, for otic and epibranchial placode induction with fgf3, for Kupffer's vesicle ciliogenesis and left-right asymmetry, and it contributes to gastrula dorsoventral patterning, mesoderm formation and restriction of endoderm, somitic fast-muscle differentiation, hindbrain patterning, retinal patterning and pharyngeal pouch and cartilage development. Heterozygous adults show craniofacial skeletal defects. In zebrafish its paralogue fgf8b shares the midbrain-hindbrain boundary and somite expression domains but is not expressed during gastrulation or in the heart. existing_annotations: - term: id: GO:0001708 label: cell fate specification evidence_type: IGI original_reference_id: PMID:12917294 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-980526-167 - ZFIN:ZDB-GENE-980526-40 review: &id001 summary: Fgf8 keeps presumptive midbrain cells from adopting forebrain fate at the diencephalic-mesencephalic boundary. action: KEEP_AS_NON_CORE reason: Scholpp et al. show that Fgf8 is necessary and sufficient to repress pax6.1 and that cells unable to receive an Fgf signal adopt forebrain fate; combined eng2/eng3 and fgf8 loss abolishes midbrain identity. Cell fate specification is a correct but generic readout of this organizer signal. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - &id014 reference_id: PMID:12917294 supporting_text: cells in the presumptive midbrain neural plate require an Fgf signal to keep them from following a forebrain fate - &id013 reference_id: PMID:12917294 supporting_text: Combined loss of both Eng2/Eng3 and Fgf8 leads to complete loss of midbrain identity, resulting in fusion of the forebrain and the hindbrain primordia. - term: id: GO:0001708 label: cell fate specification evidence_type: IGI original_reference_id: PMID:12917294 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-990415-8 review: *id001 - term: id: GO:0001708 label: cell fate specification evidence_type: IMP original_reference_id: PMID:12917294 qualifier: acts_upstream_of_or_within review: *id001 - term: id: GO:0001756 label: somitogenesis evidence_type: IGI original_reference_id: PMID:14651930 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-990415-198 review: summary: Zygotic oep;ace double mutants lack posterior tissues including somites. action: KEEP_AS_NON_CORE reason: Griffin and Kimelman show that combined loss of Zoep and ace/fgf8 abolishes all posterior tissues. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - &id010 reference_id: PMID:14651930 supporting_text: we show that Zoep and ace/fgf8 function are essential for the formation of all posterior tissues, including spinal cord. - term: id: GO:0003007 label: heart morphogenesis evidence_type: IMP original_reference_id: PMID:18639539 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: summary: fgf8 mutants have reduced heart size and altered chamber proportion. action: KEEP_AS_NON_CORE reason: Marques et al. report heart size and chamber proportion defects in fgf8 mutants; FGF signalling acts in cardiac specification and later in ventricular growth. Heart morphogenesis is a downstream consequence of the cardiac progenitor role accepted under cardioblast differentiation. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - reference_id: PMID:18639539 supporting_text: Heart size and chamber proportionality are both affected in zebrafish fgf8 mutants. - term: id: GO:0003208 label: cardiac ventricle morphogenesis evidence_type: IMP original_reference_id: PMID:10603341 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: summary: ace mutants have a severely abnormal ventricle. action: KEEP_AS_NON_CORE reason: Reifers et al. 2000 show the ventricle is particularly affected in ace mutants. The primary role is in myocardial precursor induction (accepted under cardioblast differentiation); ventricle morphogenesis is a downstream consequence. supported_by: - reference_id: PMID:10603341 supporting_text: In contrast, heart development, in particular of the ventricle, is severely abnormal in acerebellar mutants. - &id019 reference_id: PMID:10603341 supporting_text: These findings show that fgf8/acerebellar is required for induction and patterning of myocardial precursors. - term: id: GO:0005105 label: type 1 fibroblast growth factor receptor binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables supporting_entities: - PANTHER:PTN007510376 - UniProtKB:O60258 - UniProtKB:O76093 - UniProtKB:P55075 review: summary: Binding of the secreted Fgf8 ligand to FGFR1 (type 1 FGF receptor). action: ACCEPT reason: The PAINT node PTN007510376 covers the FGF8/17/18 (FgfD) clade, seeded by human FGF8, FGF17 and FGF18, whose receptor binding is experimentally established. fgf8a sits inside this clade and retains the FGF core domain; genetic and pharmacological FGFR inhibition phenocopies ace in several tissues, consistent with signalling through FGFRs. The IBA is sound for fgf8a, and equally for its paralogue fgf8b. supported_by: - &id002 reference_id: file:DANRE/fgf8a/fgf8a-uniprot.txt record_section: ["CC:FUNCTION"] supporting_text: Plays an important role in the regulation of embryonic - &id003 reference_id: PMID:9609821 supporting_text: we show that acerebellar is a zebrafish Fgf8 mutation that may inactivate Fgf8 function - term: id: GO:0005111 label: type 2 fibroblast growth factor receptor binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables supporting_entities: - PANTHER:PTN007510376 - UniProtKB:O60258 - UniProtKB:O76093 - UniProtKB:P55075 review: summary: Binding of the secreted Fgf8 ligand to FGFR2 (type 2 FGF receptor). action: ACCEPT reason: The PAINT node PTN007510376 covers the FGF8/17/18 (FgfD) clade, seeded by human FGF8, FGF17 and FGF18, whose receptor binding is experimentally established. fgf8a sits inside this clade and retains the FGF core domain; genetic and pharmacological FGFR inhibition phenocopies ace in several tissues, consistent with signalling through FGFRs. The IBA is sound for fgf8a, and equally for its paralogue fgf8b. supported_by: - *id002 - *id003 - term: id: GO:0005576 label: extracellular region evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - FB:FBgn0014135 - MGI:MGI:1099809 - MGI:MGI:1861377 - MGI:MGI:1891427 - MGI:MGI:95515 - MGI:MGI:95516 - MGI:MGI:95521 - PANTHER:PTN000160075 - RGD:2609 - RGD:2610 - RGD:61805 - RGD:620175 - RGD:620178 - UniProtKB:O15520 - UniProtKB:P05230 - UniProtKB:P09038 - UniProtKB:P31371 - UniProtKB:P48800 - UniProtKB:P55075 - UniProtKB:Q9GZV9 - WB:WBGene00001185 - WB:WBGene00002881 - ZFIN:ZDB-GENE-980526-178 - ZFIN:ZDB-GENE-990415-72 review: summary: fgf8a is a secreted ligand active in the extracellular region. action: ACCEPT reason: fgf8a has an N-terminal signal peptide, and epitope-tagged Fgf8 spreads through extracellular space in the zebrafish neuroectoderm (PMID:15498491). The IBA is well founded. supported_by: - &id006 reference_id: file:DANRE/fgf8a/fgf8a-uniprot.txt record_section: ["FT:SIGNAL"] supporting_text: SIGNAL 1..27 - &id004 reference_id: PMID:15498491 supporting_text: If internalization is inhibited, Fgf8 protein accumulates extracellularly, spreads further, and activates target gene expression over a greater distance. - term: id: GO:0005576 label: extracellular region evidence_type: IDA original_reference_id: PMID:15498491 qualifier: located_in review: summary: Tagged Fgf8 accumulates and spreads in the extracellular space of the neuroectoderm. action: ACCEPT reason: Scholpp and Brand directly visualised extracellular Fgf8 protein and showed that its extracellular range sets its signalling range. This is the functional location of the ligand. supported_by: - *id004 - &id007 reference_id: PMID:15498491 supporting_text: We find that spreading of epitope-tagged Fgf8 through target tissue is carefully controlled by endocytosis and subsequent degradation in lysosomes - term: id: GO:0005576 label: extracellular region evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0243 review: summary: Secreted (UniProt subcellular location mapping). action: ACCEPT reason: Consistent with the signal peptide and with direct observation of extracellular Fgf8 (PMID:15498491). supported_by: - &id005 reference_id: file:DANRE/fgf8a/fgf8a-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: 'SUBCELLULAR LOCATION: Secreted' - *id004 - term: id: GO:0005576 label: extracellular region evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in supporting_entities: - UniProtKB:P55075 review: summary: Secreted, by similarity to human FGF8 (P55075). action: ACCEPT reason: Transfer from human FGF8 is appropriate for the orthologue and is independently confirmed by zebrafish data (PMID:15498491). supported_by: - *id005 - *id004 - term: id: GO:0005737 label: cytoplasm evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - MGI:MGI:109178 - MGI:MGI:109189 - MGI:MGI:1914362 - MGI:MGI:95517 - MGI:MGI:95521 - PANTHER:PTN000160075 - RGD:2608 - UniProtKB:P05230 - UniProtKB:P48800 - UniProtKB:Q92913 - WB:WBGene00002881 - ZFIN:ZDB-GENE-050221-5 - ZFIN:ZDB-GENE-100316-2 - ZFIN:ZDB-GENE-990415-72 review: summary: Cytoplasm, propagated from the FGF family root node. action: MARK_AS_OVER_ANNOTATED reason: The node PTN000160075 covers the whole FGF family, including non-secreted FGF1/FGF2 and intracellular FGFs. fgf8a has a signal peptide and acts as a secreted ligand; the only intracellular location with direct evidence is lysosomes of receiving cells after endocytic clearance (PMID:15498491), which is not a site of activity. This matches the treatment of the same IBA in the human FGF8 review. supported_by: - *id006 - *id007 propagation_review: root_cause: PROPAGATION_BAD failure_modes: - COMPARTMENT_OR_COMPLEX_MISMATCH source_entities: - source_id: PANTHER:PTN000160075 source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET comment: Family-level FGF node that includes intracellular and non-classically secreted FGFs (for example FGF1, FGF2); fgf8a has a signal peptide and acts extracellularly. - term: id: GO:0005764 label: lysosome evidence_type: IDA original_reference_id: PMID:15498491 qualifier: located_in review: summary: Fgf8 protein is endocytosed by target cells and degraded in lysosomes. action: KEEP_AS_NON_CORE reason: 'The IDA is correct: tagged Fgf8 is found in lysosomes after internalisation, and this restrictive clearance shapes the gradient. The lysosome is where the ligand is degraded, not where it acts, so the location is kept as non-core.' supported_by: - *id007 - term: id: GO:0007368 label: determination of left/right symmetry evidence_type: IGI original_reference_id: PMID:19481538 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-050714-1 - ZFIN:ZDB-MRPHLNO-100511-1 review: summary: Left-right patterning, from combined fgf4/fgf8 knockdown. action: ACCEPT reason: Yamauchi et al. focus on fgf4 but state the established fgf8 requirement for Kupffer's vesicle formation. Left-right determination is a well supported fgf8a role (PMID:15932752, PMID:19164561). Accepted, consistent with the IMP row. supported_by: - reference_id: PMID:19481538 supporting_text: Fgf8 is also known to be crucial for the formation of Kupffer's vesicle, which is needed for the LR patterning of visceral organs. - &id008 reference_id: PMID:15932752 supporting_text: We find that fgf8 is required for proper asymmetric development of the brain, heart and gut. - term: id: GO:0007368 label: determination of left/right symmetry evidence_type: IMP original_reference_id: PMID:15932752 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: summary: ace/fgf8 mutants randomise brain, heart and gut laterality and often lack Kupffer's vesicle. action: ACCEPT reason: Albertson and Yelick show fgf8 is required for asymmetric development of brain, heart and gut, with loss of Kupffer's vesicle in about a third of mutants; Hong and Dawid show KV cilia depend on Fgf8 (PMID:19164561). This is one of the best established fgf8a roles. supported_by: - *id008 - &id048 reference_id: PMID:15932752 supporting_text: Approximately 1/3 of zebrafish ace/fgf8 mutants are missing Kupffer's vesicle (KV) - term: id: GO:0007420 label: brain development evidence_type: IMP original_reference_id: PMID:12843251 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: summary: ace mutants have brain defects including loss of locus coeruleus and anterior posterior-tuberculum DA neurons. action: KEEP_AS_NON_CORE reason: Full text of Holzschuh et al. confirms brain defects in ace (MHB, cerebellum, LC and late DA neuron loss). Brain development is a correct but broad term; the specific MHB role is accepted separately. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - &id024 reference_id: PMID:12843251 supporting_text: However, at 3 dpf, ace mutant embryos lack the most anterior DA neurons in the posterior tuberculum - &id023 reference_id: PMID:12843251 supporting_text: the lack-of-function ace phenotype indicates a role of FGF8 in NA neuron development in the locus coeruleus (LC) - term: id: GO:0007422 label: peripheral nervous system development evidence_type: IGI original_reference_id: PMID:17215310 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-070430-6 review: &id009 summary: fgf3/fgf8 are required for epibranchial placode induction (peripheral sensory ganglia). action: KEEP_AS_NON_CORE reason: Nechiporuk et al. show fgf3;fgf8 double mutants/morphants do not express epibranchial placode markers. The role is shared with fgf3. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - reference_id: PMID:17215310 supporting_text: zebrafish embryos mutant for fgf3 and fgf8 do not express early EB placode markers, including foxi1 and pax2a - term: id: GO:0007422 label: peripheral nervous system development evidence_type: IGI original_reference_id: PMID:17215310 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-041109-5 - ZFIN:ZDB-MRPHLNO-041109-6 - ZFIN:ZDB-MRPHLNO-050818-3 review: *id009 - term: id: GO:0007492 label: endoderm development evidence_type: IDA original_reference_id: PMID:17026981 qualifier: acts_upstream_of_or_within review: summary: Fgf signalling limits endoderm induction (IDA). action: MODIFY reason: Mizoguchi et al. show that Fgf activity negatively regulates endoderm induction via casanova. "Endoderm development" is a broad parent; the specific claim is already captured by negative regulation of endodermal cell fate specification (GO:0042664), which fgf8a also carries from PMID:16672336. supported_by: - &id035 reference_id: PMID:17026981 supporting_text: Fgf signaling negatively regulates endoderm induction, possibly through repression of cas expression and down-regulation of Cas function proposed_replacement_terms: - id: GO:0042664 label: negative regulation of endodermal cell fate specification - term: id: GO:0007492 label: endoderm development evidence_type: IMP original_reference_id: PMID:15509770 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: summary: ace mutants with reduced fgf3 fail to form pharyngeal endodermal pouches. action: KEEP_AS_NON_CORE reason: Crump et al. show Fgf8 and Fgf3 are required for pharyngeal pouch formation by endoderm. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - &id025 reference_id: PMID:15509770 supporting_text: In animals doubly reduced for Fgf8 and Fgf3, the migration of pharyngeal endodermal cells is disorganized and pouches fail to form. - term: id: GO:0007498 label: mesoderm development evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in supporting_entities: - ARBA:ARBA00084318 review: summary: Mesoderm development (ARBA machine-learning inference). action: KEEP_AS_NON_CORE reason: 'Supported for fgf8a by direct genetic evidence: ace;oep double mutants lose mesoderm (PMID:14711879, PMID:14651930). Kept as non-core, like the experimental rows for the same term.' supported_by: - &id011 reference_id: PMID:14711879 supporting_text: combining zygotic mutations in ace/fgf8 and oep disrupts mesoderm formation, a phenotype that is not produced by either mutation alone - term: id: GO:0007498 label: mesoderm development evidence_type: IGI original_reference_id: PMID:14651930 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-990415-198 review: summary: Zoep;ace double mutants lose posterior mesoderm. action: KEEP_AS_NON_CORE reason: Genetic interaction evidence from Griffin and Kimelman. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - *id010 - term: id: GO:0007498 label: mesoderm development evidence_type: IGI original_reference_id: PMID:14711879 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-070823-1 review: &id012 summary: ace and oep synergise in mesoderm formation. action: KEEP_AS_NON_CORE reason: Mathieu et al. show combined zygotic loss of ace/fgf8 and oep disrupts mesoderm, which neither single mutation does. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - *id011 - term: id: GO:0007498 label: mesoderm development evidence_type: IGI original_reference_id: PMID:14711879 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-070823-2 review: *id012 - term: id: GO:0008083 label: growth factor activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables supporting_entities: - MGI:MGI:95516 - PANTHER:PTN000160075 - RGD:2605 - RGD:2610 - RGD:61805 - RGD:620129 - RGD:620165 - RGD:71068 - UniProtKB:O15520 - UniProtKB:P05230 - UniProtKB:P09038 - UniProtKB:P55075 - WB:WBGene00002881 review: summary: Growth factor activity (FGF family IBA). action: ACCEPT reason: fgf8a is a canonical secreted FGF ligand; misexpression dorsalises embryos, induces ectopic otic tissue and rescues ace phenotypes (PMID:9609821, PMID:14757644, PMID:10603341). Core molecular function. supported_by: - *id003 - *id002 - term: id: GO:0008083 label: growth factor activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables supporting_entities: - InterPro:IPR002209 review: summary: Growth factor activity (InterPro FGF family mapping). action: ACCEPT reason: Consistent with the IBA and with experimental data. supported_by: - *id002 - term: id: GO:0008284 label: positive regulation of cell population proliferation evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - FB:FBgn0014135 - MGI:MGI:104723 - MGI:MGI:1099809 - MGI:MGI:1202401 - MGI:MGI:1277980 - MGI:MGI:1861377 - MGI:MGI:95515 - MGI:MGI:95516 - MGI:MGI:95517 - MGI:MGI:95518 - MGI:MGI:95521 - MGI:MGI:99604 - PANTHER:PTN000160075 - RGD:2605 - RGD:2608 - RGD:2609 - RGD:2610 - RGD:61805 - RGD:71052 - RGD:71068 - UniProtKB:O15520 - UniProtKB:O95750 - UniProtKB:P05230 - UniProtKB:P08620 - UniProtKB:P09038 - UniProtKB:P10767 - UniProtKB:P11487 - UniProtKB:P12034 - UniProtKB:P21781 - UniProtKB:P31371 - UniProtKB:P55075 - ZFIN:ZDB-GENE-030729-32 review: summary: Positive regulation of cell population proliferation (FGF family IBA). action: KEEP_AS_NON_CORE reason: FGFs are mitogens and Fgf8 is required for proliferation of the cerebellar territory (PMID:16611693). Kept as non-core, as in the human FGF8 review. supported_by: - &id028 reference_id: PMID:16611693 supporting_text: Fgf8 is not instructive in establishing zebrafish cerebellar cell identities, although it is required for proliferation and morphogenesis of this territory - term: id: GO:0008543 label: fibroblast growth factor receptor signaling pathway evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - FB:FBgn0014135 - MGI:MGI:104723 - MGI:MGI:1099809 - MGI:MGI:1202401 - MGI:MGI:1277980 - MGI:MGI:1861377 - MGI:MGI:1891427 - MGI:MGI:95517 - MGI:MGI:99604 - PANTHER:PTN000160075 - RGD:2609 - RGD:2610 - RGD:71052 - RGD:71068 - UniProtKB:O15520 - UniProtKB:O95750 - UniProtKB:P05230 - UniProtKB:P08620 - UniProtKB:P09038 - UniProtKB:P10767 - UniProtKB:P11487 - UniProtKB:P12034 - UniProtKB:P12226 - UniProtKB:P21781 - UniProtKB:P31371 - UniProtKB:P55075 - UniProtKB:Q8AXC5 - WB:WBGene00002881 review: summary: FGF receptor signaling pathway (IBA). action: ACCEPT reason: Core process for a FGF ligand; Fgf8 activates Ras/MAPK target genes (sef, pea3) and its loss is phenocopied by FGFR inhibition in many zebrafish tissues. supported_by: - &id017 reference_id: PMID:11802165 supporting_text: FGFs regulate dorsoventral patterning by controlling ventral bone morphogenetic protein (BMP) expression. - *id002 - term: id: GO:0009880 label: embryonic pattern specification evidence_type: IGI original_reference_id: PMID:16873584 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-000731-1 review: summary: FGF signalling is required downstream of beta-catenin/squint for organizer gene expression. action: KEEP_AS_NON_CORE reason: Maegawa et al. show FGF signalling is needed for beta-catenin induction of the organizer. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - reference_id: PMID:16873584 supporting_text: These results demonstrate that FGF signaling is necessary for beta-catenin induction of the zebrafish organizer. - term: id: GO:0009887 label: animal organ morphogenesis evidence_type: IMP original_reference_id: PMID:15932752 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: summary: ace mutants show left-right defects in visceral organ and pharyngeal skeleton morphogenesis. action: KEEP_AS_NON_CORE reason: Animal organ morphogenesis is a broad grouping term for the laterality defects of brain, heart and gut in ace (accepted more specifically as determination of left/right symmetry). supported_by: - *id008 - term: id: GO:0009952 label: anterior/posterior pattern specification evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in supporting_entities: - ARBA:ARBA00027259 review: summary: Anterior/posterior pattern specification (ARBA). action: KEEP_AS_NON_CORE reason: Supported for fgf8a by experimental evidence on midbrain/forebrain boundary positioning and hindbrain patterning (PMID:12917294, PMID:14745965). Kept as non-core, like the experimental rows for the same term. supported_by: - *id013 - &id029 reference_id: PMID:14745965 supporting_text: These data demonstrate an early, nonredundant requirement for fgf8 function in hindbrain patterning. - term: id: GO:0009952 label: anterior/posterior pattern specification evidence_type: IGI original_reference_id: PMID:12917294 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-980526-167 - ZFIN:ZDB-GENE-980526-40 review: &id015 summary: Fgf8 positions the diencephalic-mesencephalic boundary along the A/P axis. action: KEEP_AS_NON_CORE reason: 'Scholpp et al.: Fgf8 represses pax6.1 and shifts the DMB anteriorly; with eng2/eng3 it maintains midbrain identity. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity.' supported_by: - *id013 - *id014 - term: id: GO:0009952 label: anterior/posterior pattern specification evidence_type: IGI original_reference_id: PMID:12917294 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-990415-8 review: *id015 - term: id: GO:0009952 label: anterior/posterior pattern specification evidence_type: IGI original_reference_id: PMID:15342476 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-020104-1 - ZFIN:ZDB-GENE-980526-178 review: summary: Fgf signals from r4 act with vhnf1 in caudal hindbrain A/P patterning. action: KEEP_AS_NON_CORE reason: Hernandez et al. show Fgf from r4 cooperates with Vhnf1 to specify r5/r6. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - reference_id: PMID:15342476 supporting_text: Fgf signals from r4, acting through the MapK pathway, then cooperate with Vhnf1 to activate val expression and subsequent r5 and r6 development. - term: id: GO:0009952 label: anterior/posterior pattern specification evidence_type: IMP original_reference_id: PMID:12917294 qualifier: acts_upstream_of_or_within review: *id015 - term: id: GO:0009953 label: dorsal/ventral pattern formation evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - MGI:MGI:99604 - PANTHER:PTN002608342 - ZFIN:ZDB-GENE-030708-1 - ZFIN:ZDB-GENE-990415-72 review: summary: Dorsal/ventral pattern formation (IBA, FgfD node). action: KEEP_AS_NON_CORE reason: The node PTN002608342 is seeded by zebrafish fgf8a and fgf24 and by mouse Fgf8. fgf8a is expressed in a dorsoventral gradient during gastrulation and its loss enhances chordin ventralisation (PMID:9609821, PMID:15151985), so the IBA is right for fgf8a. Non-core as for human FGF8. supported_by: - &id016 reference_id: PMID:15151985 supporting_text: we show that loss of Fgf8 function enhances the ventralisation of chordin-deficient embryos - term: id: GO:0009953 label: dorsal/ventral pattern formation evidence_type: IDA original_reference_id: PMID:16890217 qualifier: acts_upstream_of_or_within review: summary: D/V axis patterning (IDA, from a noggin/follistatin-like paper). action: KEEP_AS_NON_CORE reason: The cached abstract of PMID:16890217 does not mention fgf8, but D/V patterning by fgf8a is established (PMID:15151985, PMID:9609821). Deferring to the curator, who read the full text. supported_by: - *id016 - term: id: GO:0009953 label: dorsal/ventral pattern formation evidence_type: IGI original_reference_id: PMID:15151985 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-990415-33 review: &id018 summary: Loss of Fgf8 enhances the ventralisation of chordin mutants. action: KEEP_AS_NON_CORE reason: Furthauer et al. show pre-gastrula Fgf signalling restricts bmp expression and that loss of Fgf8 function enhances chordin ventralisation. Gastrula D/V patterning is a well established fgf8a role, and one that the paralogue fgf8b cannot share in vivo because it is not expressed during gastrulation (PMID:11091072). Kept as non-core, consistent with the other rows for this term and with the human FGF8 review. Kept as non-core, consistent with the other rows for this term and with the human FGF8 review. supported_by: - *id016 - reference_id: PMID:11091072 supporting_text: fgf17 can act similar to fgf8 during gastrulation, when fgf17 is not normally expressed - term: id: GO:0009953 label: dorsal/ventral pattern formation evidence_type: IMP original_reference_id: PMID:11802165 qualifier: acts_upstream_of_or_within review: summary: D/V patterning, from the Sef paper. action: KEEP_AS_NON_CORE reason: Furthauer et al. 2002 describe FGF regulation of ventral BMP expression and Sef as a feedback antagonist of Fgf8 signalling. Consistent with the accepted D/V role. supported_by: - *id017 - term: id: GO:0009953 label: dorsal/ventral pattern formation evidence_type: IMP original_reference_id: PMID:15151985 qualifier: acts_upstream_of_or_within review: *id018 - term: id: GO:0010002 label: cardioblast differentiation evidence_type: IMP original_reference_id: PMID:10603341 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: summary: fgf8 is required for initiation of nkx2.5 and gata4 in cardiac precursors. action: ACCEPT reason: 'Reifers et al. 2000 show fgf8 is expressed in and required for heart precursors, with rescue by fgf8 RNA or Fgf8 beads. In zebrafish this cardiac role belongs to fgf8a only: fgf8b is not expressed in the heart (PMID:19562753).' supported_by: - *id019 - term: id: GO:0014709 label: positive regulation of somitomeric trunk muscle development evidence_type: IMP original_reference_id: PMID:16120642 qualifier: involved_in review: summary: Fgf8 drives terminal differentiation of lateral fast muscle. action: KEEP_AS_NON_CORE reason: Groves et al. show Fgf8 signalling in the somite is required for myod expression and differentiation of lateral fast muscle fibres. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - &id044 reference_id: PMID:16120642 supporting_text: we show that Fgf8 signalling in the somite is required for myod expression and terminal differentiation of a subset of fast muscle cells in the zebrafish lateral somite - term: id: GO:0021549 label: cerebellum development evidence_type: IMP original_reference_id: PMID:22223680 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-050714-1 review: summary: Cerebellum development (fgf8 morphants, grhl2b paper). action: ACCEPT reason: Cerebellum development is the defining ace phenotype (PMID:9609821, PMID:9007239); the curator of PMID:22223680 recorded it from fgf8 morphants. supported_by: - &id020 reference_id: PMID:22223680 supporting_text: Formation and maintenance of the MHB is characterised by a hierarchical program of gene expression initiated by fibroblast growth factor 8 (Fgf8) - &id022 reference_id: PMID:9609821 supporting_text: Homozygous acerebellar embryos lack a cerebellum and the midbrain-hindbrain boundary organizer. - term: id: GO:0021555 label: midbrain-hindbrain boundary morphogenesis evidence_type: IGI original_reference_id: PMID:22223680 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-050714-1 - ZFIN:ZDB-MRPHLNO-120207-2 review: summary: MHB morphogenesis, genetic interaction of fgf8 and grhl2b. action: ACCEPT reason: Dworkin et al. place Fgf8 at the top of the MHB gene-expression hierarchy; the IGI records its interaction with grhl2b in MHB folding. Consistent with the core MHB organizer role. supported_by: - *id020 - term: id: GO:0021571 label: rhombomere 5 development evidence_type: IGI original_reference_id: PMID:12835397 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-050714-1 - ZFIN:ZDB-MRPHLNO-050818-4 review: &id021 summary: Fgf signals synergise with vhnf1 to specify rhombomeres 5 and 6. action: KEEP_AS_NON_CORE reason: Wiellette and Sive show vhnf1 acts in obligate synergy with Fgf signals in r5/r6 specification. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - reference_id: PMID:12835397 supporting_text: vhnf1 promotes r5+r6 identity through an obligate synergy with Fgf signals to activate valentino and krox20 expression - term: id: GO:0021572 label: rhombomere 6 development evidence_type: IGI original_reference_id: PMID:12835397 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-050714-1 - ZFIN:ZDB-MRPHLNO-050818-4 review: *id021 - term: id: GO:0021588 label: cerebellum formation evidence_type: IMP original_reference_id: PMID:12591239 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: summary: ace mutants lack a cerebellum; wnt1/wnt10b-deficient embryos are sensitised to loss of Fgf8. action: ACCEPT reason: Loss of the cerebellum is the defining acerebellar phenotype. supported_by: - *id022 - reference_id: PMID:12591239 supporting_text: Embryos homozygous for the wnt1-wnt10b deficiency display a mild MHB phenotype, but are sensitized to reductions in either Pax2.1 or Fgf8; that is, in combination with mutant alleles of either of these loci, the morphological MHB is lost. - term: id: GO:0021703 label: locus ceruleus development evidence_type: IGI original_reference_id: PMID:17215310 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-041109-5 - ZFIN:ZDB-MRPHLNO-041109-6 - ZFIN:ZDB-MRPHLNO-050818-3 review: summary: Locus coeruleus, from fgf3/fgf8 knockdown in the epibranchial placode paper. action: KEEP_AS_NON_CORE reason: The cached abstract does not mention the LC, but the absence of the LC in ace mutants is independently established (PMID:12843251, PMID:10595509). Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - *id023 - term: id: GO:0021703 label: locus ceruleus development evidence_type: IMP original_reference_id: PMID:10595509 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: summary: Phox2a in LC progenitors depends on Fgf8 from the MHB. action: KEEP_AS_NON_CORE reason: Guo et al. show LC specification depends on FGF8 from the MHB. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - reference_id: PMID:10595509 supporting_text: its expression there is dependent on FGF8 from the mid/hindbrain boundary - *id023 - term: id: GO:0022008 label: neurogenesis evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - FB:FBgn0014135 - MGI:MGI:109178 - MGI:MGI:1099809 - MGI:MGI:1891346 - MGI:MGI:95516 - MGI:MGI:95519 - MGI:MGI:99604 - PANTHER:PTN000160075 - RGD:70891 - UniProtKB:A6P7H6 - UniProtKB:P48800 - UniProtKB:P55075 - ZFIN:ZDB-GENE-030729-32 - ZFIN:ZDB-GENE-050208-380 - ZFIN:ZDB-GENE-060427-3 - ZFIN:ZDB-GENE-980526-178 - ZFIN:ZDB-GENE-990415-72 review: summary: Neurogenesis (FGF family IBA). action: KEEP_AS_NON_CORE reason: Correct in outline (MHB organizer, LC and 5HT neuron development) but broad; non-core as for human FGF8. supported_by: - &id030 reference_id: PMID:15281067 supporting_text: Hindbrain 5HT neurons are severely reduced in mutants lacking activity of either Ace/Fgf8 or the transcription factor Noi/Pax2.1 - term: id: GO:0030177 label: positive regulation of Wnt signaling pathway evidence_type: IGI original_reference_id: PMID:14757644 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-980526-178 review: summary: Positive regulation of Wnt signaling (IGI with fgf3). action: UNDECIDED reason: 'The cached abstract of Phillips et al. describes the reverse relationship: Wnt8 regulates the timely expression of fgf3 and fgf8 in the hindbrain, and Fgf, not Wnt, acts on preotic cells. I cannot see the result on which the curator based an Fgf8-upstream-of-Wnt annotation, so I neither accept nor remove it.' supported_by: - reference_id: PMID:14757644 supporting_text: We propose that Wnt8 serves to regulate timely expression of Fgf3 and Fgf8 in the hindbrain, and that Fgf from the hindbrain then acts directly on preplacodal cells to induce otic differentiation. - term: id: GO:0030182 label: neuron differentiation evidence_type: IMP original_reference_id: PMID:12843251 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: summary: ace mutants lose LC noradrenergic neurons and late anterior DA neurons. action: KEEP_AS_NON_CORE reason: 'Full text of Holzschuh et al.: Fgf8 is not needed to specify the earliest DA neurons, but ace mutants lack LC neurons and later lose anterior posterior-tuberculum DA neurons. Neuron differentiation is a correct broad readout. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity.' supported_by: - *id023 - *id024 - term: id: GO:0030334 label: regulation of cell migration evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - MGI:MGI:1099809 - MGI:MGI:95516 - PANTHER:PTN000160075 - RGD:2610 - UniProtKB:O15520 - UniProtKB:O43320 - UniProtKB:O76093 - UniProtKB:P05230 - UniProtKB:P08620 - UniProtKB:P09038 - UniProtKB:P21781 - WB:WBGene00001185 - ZFIN:ZDB-GENE-980526-178 - ZFIN:ZDB-GENE-990415-72 review: summary: Regulation of cell migration (FGF family IBA). action: KEEP_AS_NON_CORE reason: 'Supported in zebrafish: Fgf8a acts as a guidance cue for migrating pharyngeal pouch cells (PMID:25142463). Non-core.' supported_by: - &id026 reference_id: PMID:25142463 supporting_text: Fgf8a acts as a Wnt11r-dependent guidance cue for migrating pouch cells - term: id: GO:0030335 label: positive regulation of cell migration evidence_type: IGI original_reference_id: PMID:15509770 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-980526-178 review: summary: Fgf8 with fgf3 directs lateral migration of pharyngeal endoderm. action: KEEP_AS_NON_CORE reason: Crump et al. show that endodermal cell migration is disorganised when Fgf8 and Fgf3 are reduced; Choe and Crump later identify Fgf8a as a guidance cue for pouch cells. supported_by: - *id025 - *id026 - term: id: GO:0030878 label: thyroid gland development evidence_type: IMP original_reference_id: PMID:17611226 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: summary: ace mutants have thyroid defects. action: KEEP_AS_NON_CORE reason: Wendl et al. report thyroid defects in ace mutants like those of hand2 mutants, with FGF acting from surrounding tissue. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - reference_id: PMID:17611226 supporting_text: The zebrafish ace (fgf8) mutant has similar thyroid defects as han mutants - term: id: GO:0030901 label: midbrain development evidence_type: IGI original_reference_id: PMID:12917294 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-980526-167 - ZFIN:ZDB-GENE-980526-40 review: &id027 summary: Fgf8 maintains midbrain identity and positions the diencephalic-mesencephalic boundary. action: ACCEPT reason: 'Scholpp et al.: combined loss of Eng2/Eng3 and Fgf8 abolishes midbrain identity. Midbrain patterning is part of the MHB organizer function that defines fgf8a.' supported_by: - *id013 - *id014 - term: id: GO:0030901 label: midbrain development evidence_type: IGI original_reference_id: PMID:12917294 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-990415-8 review: *id027 - term: id: GO:0030901 label: midbrain development evidence_type: IGI original_reference_id: PMID:23789101 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-041109-4 - ZFIN:ZDB-MRPHLNO-050714-1 review: summary: fgf3/fgf8 are required for fgf22 expression and midbrain development. action: ACCEPT reason: 'Miyake and Itoh: fgf3/fgf8 double morphants resemble fgf22 morphants and Fgf3/Fgf8 are needed for fgf22 expression in the posterior midbrain. Part of the MHB organizer role.' supported_by: - reference_id: PMID:23789101 supporting_text: Fgf3/Fgf8 signaling was required for fgf22 expression in the posterior midbrain - term: id: GO:0030901 label: midbrain development evidence_type: IMP original_reference_id: PMID:12917294 qualifier: acts_upstream_of_or_within review: *id027 - term: id: GO:0030902 label: hindbrain development evidence_type: IGI original_reference_id: PMID:16611693 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 - ZFIN:ZDB-MRPHLNO-060620-3 - ZFIN:ZDB-MRPHLNO-060620-5 review: &id031 summary: Fgf8 is required for proliferation and morphogenesis of the cerebellar (r1) territory. action: KEEP_AS_NON_CORE reason: 'Foucher et al.: Fgf8 maintains the posterior Otx boundary and supports proliferation but is not instructive for cerebellar identities. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity.' supported_by: - *id028 - term: id: GO:0030902 label: hindbrain development evidence_type: IMP original_reference_id: PMID:14745965 qualifier: acts_upstream_of_or_within review: summary: Early, nonredundant requirement for fgf8 in r5/r6 specification. action: KEEP_AS_NON_CORE reason: Wiellette and Sive 2004 show ace mutation and fgf8 MO both suppress r5/r6 genes at early somitogenesis. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - *id029 - term: id: GO:0030902 label: hindbrain development evidence_type: IMP original_reference_id: PMID:15281067 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: summary: ace mutants have severely reduced hindbrain 5HT neurons. action: KEEP_AS_NON_CORE reason: Teraoka et al. report loss of hindbrain serotonergic neurons in ace. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - *id030 - term: id: GO:0030902 label: hindbrain development evidence_type: IMP original_reference_id: PMID:16611693 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: *id031 - term: id: GO:0030903 label: notochord development evidence_type: IGI original_reference_id: PMID:14651930 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-990415-198 review: summary: Zoep;ace double mutants lack posterior tissues, including notochord. action: KEEP_AS_NON_CORE reason: Genetic interaction evidence from Griffin and Kimelman. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - *id010 - term: id: GO:0030916 label: otic vesicle formation evidence_type: IDA original_reference_id: PMID:17239227 qualifier: acts_upstream_of_or_within review: summary: Heat-shock fgf8 misexpression at the end of gastrulation enlarges otic vesicles. action: KEEP_AS_NON_CORE reason: Gain-of-function evidence (recorded as IDA) from Hans et al.; it shows sufficiency within the competent field. Otic induction by fgf8a is accepted under otic placode formation. supported_by: - reference_id: PMID:17239227 supporting_text: fgf8 overexpression at the end of gastrulation, when otic induction begins, leads to much larger otic vesicles - term: id: GO:0030916 label: otic vesicle formation evidence_type: IGI original_reference_id: PMID:15188428 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-980526-178 review: &id032 summary: fgf8 interacts genetically with foxi1, fgf3 and dlx3b in otic induction. action: KEEP_AS_NON_CORE reason: Solomon et al. report strong synergy among foxi1, fgf3 and fgf8 and weaker synergy with dlx3b. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - reference_id: PMID:15188428 supporting_text: A strong synergistic interaction is also observed among foxi1, fgf3, and fgf8 - term: id: GO:0030916 label: otic vesicle formation evidence_type: IGI original_reference_id: PMID:15188428 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-980526-280 review: *id032 - term: id: GO:0030916 label: otic vesicle formation evidence_type: IGI original_reference_id: PMID:15188428 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-030617-1 review: *id032 - term: id: GO:0030916 label: otic vesicle formation evidence_type: IMP original_reference_id: PMID:14757644 qualifier: acts_upstream_of_or_within review: summary: Fgf3/Fgf8 depletion abolishes otic tissue. action: KEEP_AS_NON_CORE reason: Phillips et al. show embryos depleted for Fgf3 and Fgf8 form no otic tissue. supported_by: - reference_id: PMID:14757644 supporting_text: Embryos that misexpress Wnt8 globally but are depleted for Fgf3 and Fgf8 produce no otic tissue. - term: id: GO:0030917 label: midbrain-hindbrain boundary development evidence_type: IMP original_reference_id: PMID:12591239 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: &id033 summary: acerebellar mutants lack the MHB and isthmic organizer. action: ACCEPT reason: 'The defining fgf8a phenotype: ace embryos lack the MHB constriction and the isthmic organizer; isthmic and cerebellar primordia take tectal identity; Fgf8 beads rescue. Core in vivo role of fgf8a.' supported_by: - *id022 - reference_id: PMID:9007239 supporting_text: 'The defect in ace mutant embryos is more restricted: MHB and cerebellum are absent, but a tectum is formed.' - reference_id: PMID:14660549 supporting_text: cells of the isthmic and cerebellar primordia acquire a more rostral, tectal identity in the absence of the functional MHB organizer signal Fgf8 - term: id: GO:0030917 label: midbrain-hindbrain boundary development evidence_type: IMP original_reference_id: PMID:14660549 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: *id033 - term: id: GO:0030917 label: midbrain-hindbrain boundary development evidence_type: IMP original_reference_id: PMID:28493069 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-041109-5 review: summary: fgf8a morphants lose epha4a at the MHB/r1 boundary. action: ACCEPT reason: Zhang et al. (full text) used fgf8a morpholinos and saw loss of epha4a in r1 and ectopic midbrain pax6a, consistent with the ace MHB phenotype. supported_by: - reference_id: PMID:28493069 supporting_text: Epha4a expression in rhombomere R1 boundary was decreased in chronic ethanol exposure and aldh1a3 morphants, lost in fgf8a morphants - term: id: GO:0030917 label: midbrain-hindbrain boundary development evidence_type: IMP original_reference_id: PMID:9007239 qualifier: acts_upstream_of_or_within review: *id033 - term: id: GO:0030917 label: midbrain-hindbrain boundary development evidence_type: IMP original_reference_id: PMID:9609821 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: *id033 - term: id: GO:0031076 label: embryonic camera-type eye development evidence_type: IMP original_reference_id: PMID:16236770 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: summary: Fgf8 from the telencephalon patterns the nasotemporal axis of the retina. action: KEEP_AS_NON_CORE reason: Picker and Brand show Fgf8 induces nasal retinal fates. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - reference_id: PMID:16236770 supporting_text: Fgf8 induces nasal and/or suppresses temporal retinal cell fates - term: id: GO:0035050 label: embryonic heart tube development evidence_type: IGI original_reference_id: PMID:16672336 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-548 - ZFIN:ZDB-MRPHLNO-050714-1 - ZFIN:ZDB-MRPHLNO-060328-4 review: summary: Heart tube development, genetic interaction in the endoderm/Nodal paper. action: KEEP_AS_NON_CORE reason: The cached abstract of Poulain et al. concerns endoderm restriction by FGF/ERK and BMP; the heart tube phenotype was presumably recorded from the full text. fgf8a is required for heart development (PMID:10603341), so I defer to the curator. supported_by: - *id019 - &id034 reference_id: PMID:16672336 supporting_text: BMP and FGF-ERK pathways cooperate to restrict the number of endodermal progenitors induced in response to Nodal signalling - term: id: GO:0042664 label: negative regulation of endodermal cell fate specification evidence_type: IDA original_reference_id: PMID:16672336 qualifier: acts_upstream_of_or_within review: &id036 summary: FGF/ERK signalling restricts the number of Nodal-induced endoderm progenitors. action: KEEP_AS_NON_CORE reason: Poulain et al. show FGF/ERK and BMP cooperate to limit endoderm precursors, via phosphorylation of Casanova/Sox32. This is a gastrula-stage role of fgf8a that fgf8b, not expressed until mid-somitogenesis, cannot share. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - *id034 - term: id: GO:0042664 label: negative regulation of endodermal cell fate specification evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in supporting_entities: - ARBA:ARBA00086809 review: summary: Negative regulation of endodermal cell fate specification (ARBA). action: KEEP_AS_NON_CORE reason: Consistent with the experimental rows from PMID:16672336 and PMID:17026981. Kept as non-core, like the experimental rows for the same term. supported_by: - *id034 - *id035 - term: id: GO:0042664 label: negative regulation of endodermal cell fate specification evidence_type: IGI original_reference_id: PMID:16672336 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-011026-1 review: *id036 - term: id: GO:0042664 label: negative regulation of endodermal cell fate specification evidence_type: IGI original_reference_id: PMID:16672336 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-991206-8 - ZFIN:ZDB-MRPHLNO-050714-1 - ZFIN:ZDB-MRPHLNO-060328-4 - ZFIN:ZDB-MRPHLNO-060731-3 review: *id036 - term: id: GO:0042664 label: negative regulation of endodermal cell fate specification evidence_type: IGI original_reference_id: PMID:16672336 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-050714-1 - ZFIN:ZDB-MRPHLNO-060328-4 - ZFIN:ZDB-MRPHLNO-060731-3 review: *id036 - term: id: GO:0043049 label: otic placode formation evidence_type: IGI original_reference_id: PMID:12642489 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-980526-178 review: summary: Otic placode formation, from the squint/cyclops paper. action: ACCEPT reason: The cached abstract of Dougan et al. does not mention fgf8, but fgf8a function in otic placode induction is well established (PMID:17522161, PMID:14757644), so I defer to the curator. supported_by: - &id037 reference_id: PMID:17522161 supporting_text: fgf8 mutants depleted of RA signaling produce few otic cells, and these cells fail to form a vesicle, indicating that Fgf8 is the primary factor responsible for otic induction in RA-depleted embryos - term: id: GO:0043049 label: otic placode formation evidence_type: IGI original_reference_id: PMID:15459102 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-001030-3 review: &id038 summary: Otic placode formation (pax8/pax2a paper). action: ACCEPT reason: Hans et al. 2004 place Pax2a and Pax8 downstream of Fgf signals in otic induction. fgf8a is one of the two inducing Fgfs, with fgf3. supported_by: - reference_id: PMID:15459102 supporting_text: competent ectodermal cells respond to Fgf signals from adjacent tissues and express two highly related paired box transcription factors Pax2a and Pax8 in the developing placode - *id037 - term: id: GO:0043049 label: otic placode formation evidence_type: IMP original_reference_id: PMID:15459102 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: *id038 - term: id: GO:0043049 label: otic placode formation evidence_type: IMP original_reference_id: PMID:17522161 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-070430-3 review: &id039 summary: fgf8 mutants depleted of RA form few otic cells and no vesicle. action: ACCEPT reason: Hans and Westerfield identify Fgf8 as the primary otic inducer in RA-depleted embryos. supported_by: - *id037 - term: id: GO:0043049 label: otic placode formation evidence_type: IMP original_reference_id: PMID:17522161 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: *id039 - term: id: GO:0043049 label: otic placode formation evidence_type: IMP original_reference_id: PMID:24677486 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-101119-36 review: summary: Otic induction in fgf8 x15 mutants with fgf10b knockdown. action: ACCEPT reason: Maulding et al. (full text) use the fgf8 x15 mutant; otic induction by Fgf3 and Fgf8 is conserved across species. supported_by: - &id049 reference_id: PMID:24677486 supporting_text: the process of otic induction in highly conserved, with important roles for Fgf3 and Fgf8 reported in all species examined - term: id: GO:0043410 label: positive regulation of MAPK cascade evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - MGI:MGI:1099809 - MGI:MGI:1277980 - MGI:MGI:1861377 - MGI:MGI:1891427 - MGI:MGI:95516 - MGI:MGI:99604 - PANTHER:PTN000160075 - RGD:2609 - RGD:71068 - UniProtKB:O15520 - UniProtKB:O76093 - UniProtKB:O95750 - UniProtKB:P05230 - UniProtKB:P08620 - UniProtKB:P09038 - UniProtKB:Q9NSA1 review: summary: Positive regulation of MAPK cascade (IBA). action: ACCEPT reason: FGF ligands activate Ras/MAPK; Sef was identified as a feedback antagonist of Fgf8-induced Ras/MAPK signalling (PMID:11802165). supported_by: - *id017 - term: id: GO:0046850 label: regulation of bone remodeling evidence_type: IEP original_reference_id: PMID:17448458 qualifier: acts_upstream_of_or_within review: summary: Regulation of bone remodeling, from fgf8 expression in the adult craniofacial skeleton (IEP). action: MARK_AS_OVER_ANNOTATED reason: Expression of fgf8 in adult craniofacial bone is consistent with a role there but cannot by itself show regulation of bone remodeling. The functional claim rests on the IMP from the same paper, which is kept. supported_by: - reference_id: PMID:17448458 supporting_text: skeletal defects observed in ace(ti282a)/fgf8 heterozygotes are consistent with expression patterns of fgf8 in the mature craniofacial skeleton - term: id: GO:0046850 label: regulation of bone remodeling evidence_type: IMP original_reference_id: PMID:17448458 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-070524-7 review: summary: ace/fgf8 heterozygous adults show craniofacial skeletal defects and increased bone metabolism. action: KEEP_AS_NON_CORE reason: Albertson and Yelick (full text) describe haploinsufficient adult skeletal phenotypes. The ace ti282a allele carries a premature stop codon. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - &id041 reference_id: PMID:17448458 supporting_text: may be related to increased levels of bone metabolism observed in ace(ti282a)/fgf8 heterozygotes - term: id: GO:0048263 label: determination of dorsal identity evidence_type: IDA original_reference_id: PMID:16961592 qualifier: acts_upstream_of_or_within review: summary: fgf8 mRNA injection dorsalises embryos (both splice isoforms). action: KEEP_AS_NON_CORE reason: 'Inoue et al. show both Fgf8 splice variants dorsalise the embryo. Gain-of-function data consistent with the D/V role. Note: "Fgf8a/Fgf8b" in this paper are splice isoforms of fgf8a, not the paralogues.' supported_by: - reference_id: PMID:16961592 supporting_text: both variants have dorsalizing activities on zebrafish embryos, with Fgf8b being more potent - term: id: GO:0048339 label: paraxial mesoderm development evidence_type: IGI original_reference_id: PMID:14651930 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-990415-198 review: summary: Paraxial mesoderm development, Zoep;ace interaction. action: KEEP_AS_NON_CORE reason: Genetic interaction from Griffin and Kimelman. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - *id010 - term: id: GO:0048339 label: paraxial mesoderm development evidence_type: IGI original_reference_id: PMID:32345657 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-201021-2 review: &id040 summary: Fgf signalling acts through Tbx16/Tbxta to initiate trunk myogenesis in paraxial mesoderm. action: KEEP_AS_NON_CORE reason: Osborn et al. (full text) show dorsally derived Fgf signals act through Tbx16 and Tbxta to induce muscle precursors. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - reference_id: PMID:32345657 supporting_text: dorsally derived Fgf signals act through Tbx16 and Tbxta to induce slow and fast trunk muscle precursors at distinct dorsoventral positions - term: id: GO:0048339 label: paraxial mesoderm development evidence_type: IGI original_reference_id: PMID:32345657 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-201022-1 review: *id040 - term: id: GO:0048665 label: neuron fate specification evidence_type: IGI original_reference_id: PMID:16256099 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-041109-4 - ZFIN:ZDB-MRPHLNO-050714-1 review: summary: Neuron fate specification, fgf3/fgf8 knockdown in the Fgf19 paper. action: UNDECIDED reason: The cached abstract of Miyake et al. concerns Fgf19 and mentions Fgf3/Fgf8 only as upstream brain-patterning signals that do not control fgf19 expression. I cannot see the fgf3/fgf8 double-knockdown result on which this annotation rests. supported_by: - &id042 reference_id: PMID:16256099 supporting_text: Fgf3 and Fgf8 are crucial for the formation of the forebrain and hindbrain. - term: id: GO:0048702 label: embryonic neurocranium morphogenesis evidence_type: IGI original_reference_id: PMID:27060628 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-980526-178 review: summary: Fgf signalling specifies mesodermal progenitors of the postchordal neurocranium. action: KEEP_AS_NON_CORE reason: McCarthy et al. show early Fgf signalling is needed for has2 expression in cephalic mesoderm and postchordal neurocranium development. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - reference_id: PMID:27060628 supporting_text: Fibroblast growth factor (Fgf) signaling for early specification of mesodermally-derived progenitor cells - term: id: GO:0048705 label: skeletal system morphogenesis evidence_type: IMP original_reference_id: PMID:17448458 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-070524-7 review: summary: Craniofacial skeletal defects in adult ace heterozygotes. action: KEEP_AS_NON_CORE reason: Adult haploinsufficiency phenotype. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - *id041 - term: id: GO:0048709 label: oligodendrocyte differentiation evidence_type: IGI original_reference_id: PMID:16256099 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-041109-4 - ZFIN:ZDB-MRPHLNO-050714-1 review: summary: Oligodendrocyte differentiation, fgf3/fgf8 knockdown in the Fgf19 paper. action: UNDECIDED reason: 'As for neuron fate specification from the same paper: the cached abstract does not show the fgf3/fgf8 result.' supported_by: - *id042 - term: id: GO:0048839 label: inner ear development evidence_type: IMP original_reference_id: PMID:16754885 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-050714-1 review: summary: fgf8 loss gives fused otoliths and abnormal semicircular canals. action: KEEP_AS_NON_CORE reason: Asai et al. describe the inner-ear phenotype of fgf8 loss, which the atrophin2 mutant resembles. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - &id043 reference_id: PMID:16754885 supporting_text: 'whose phenotypic characteristics resembled those of null mutants for the gene encoding fibroblast growth factor 8 (Fgf8): an inconsistent startle response, circular swimming, fused otoliths, and abnormal semicircular canals' - term: id: GO:0048839 label: inner ear development evidence_type: IMP original_reference_id: PMID:9007239 qualifier: acts_upstream_of_or_within review: summary: Inner ear development, from the original ace screen paper. action: KEEP_AS_NON_CORE reason: The cached abstract of Brand et al. 1996 focuses on MHB; ear defects of fgf8 loss are documented elsewhere (PMID:16754885). Deferring to the curator. supported_by: - *id043 - term: id: GO:0051146 label: striated muscle cell differentiation evidence_type: IMP original_reference_id: PMID:16120642 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: &id045 summary: Fgf8 is required for differentiation of lateral fast muscle fibres. action: KEEP_AS_NON_CORE reason: Groves et al. (ace mutants and morphants). Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - *id044 - term: id: GO:0051146 label: striated muscle cell differentiation evidence_type: IMP original_reference_id: PMID:16120642 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-050714-1 review: *id045 - term: id: GO:0051216 label: cartilage development evidence_type: IMP original_reference_id: PMID:14651935 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-050714-1 review: summary: fgf8 knockdown has mild cartilage effects, severe when combined with fgf3. action: KEEP_AS_NON_CORE reason: 'Walshe and Mason: Fgf8 inhibition alone has variable, mild effects on head cartilage; with Fgf3 inhibition all pharyngeal cartilage is lost. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity.' supported_by: - reference_id: PMID:14651935 supporting_text: Inhibition of Fgf8 alone has variable, but mild, effects. However, inhibition of both Fgf3 and Fgf8 together causes a complete absence of pharyngeal cartilages and the near-complete loss of the neurocranial cartilage. - term: id: GO:0051216 label: cartilage development evidence_type: IMP original_reference_id: PMID:15509770 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: summary: Fgf8/Fgf3 reduction causes hyoid and branchial cartilage loss. action: KEEP_AS_NON_CORE reason: Crump et al. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - reference_id: PMID:15509770 supporting_text: animals doubly reduced for Fgf8 and Fgf3 have severe reductions in hyoid cartilages and the more posterior branchial cartilages - term: id: GO:0051216 label: cartilage development evidence_type: IMP original_reference_id: PMID:16754885 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-050714-1 review: summary: Cartilage development (atrophin2 paper). action: KEEP_AS_NON_CORE reason: Asai et al. (full text) include fgf8 morphants as a comparison for the atrophin2 phenotype. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - *id043 - term: id: GO:0055011 label: atrial cardiac muscle cell differentiation evidence_type: IMP original_reference_id: PMID:19395641 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-090527-5 - ZFIN:ZDB-MRPHLNO-041109-6 negated: true review: summary: 'NOT: fgf8 is not required for atrial (venous pole) cardiomyocyte addition.' action: ACCEPT reason: De Pater et al. show fgf8 morphants lose late-differentiating cardiomyocytes at the arterial pole but not at the venous pole. The negated annotation is supported. supported_by: - &id046 reference_id: PMID:19395641 supporting_text: Our data demonstrate that cardiomyocyte differentiation at the arterial pole is independent of Isl1 but requires Fgf8 signaling. - reference_id: PMID:19395641 supporting_text: while the number of eGFP pos DsRed neg cells at the venous pole did not change significantly - term: id: GO:0055012 label: ventricular cardiac muscle cell differentiation evidence_type: IMP original_reference_id: PMID:19395641 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-090527-5 - ZFIN:ZDB-MRPHLNO-041109-6 review: summary: Late cardiomyocyte addition at the arterial pole requires Fgf8. action: KEEP_AS_NON_CORE reason: De Pater et al. (full text). Refines the accepted cardiac progenitor role. supported_by: - *id046 - term: id: GO:0060037 label: pharyngeal system development evidence_type: IGI original_reference_id: PMID:17576618 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-071012-3 review: summary: rerea interacts genetically with fgf8 in pharyngeal development. action: KEEP_AS_NON_CORE reason: 'Plaster et al.: loss of REREa or HDAC synergises with loss of Fgf8 in pharyngeal cartilage and other tissues. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity.' supported_by: - reference_id: PMID:17576618 supporting_text: removing the functions of either REREa or HDAC synergizes with loss of Fgf8 function to disrupt posterior mesoderm formation during somitogenesis, midbrain-hindbrain boundary maintenance, and pharyngeal cartilage development - term: id: GO:0060037 label: pharyngeal system development evidence_type: IGI original_reference_id: PMID:25142463 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-030805-5 review: summary: Mesodermal Fgf8a guides pharyngeal pouch morphogenesis downstream of Tbx1. action: KEEP_AS_NON_CORE reason: 'Choe and Crump (full text): compound loss of wnt11r and fgf8a phenocopies tbx1 pouch defects, and Fgf8a is a guidance cue for migrating pouch cells. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity.' supported_by: - reference_id: PMID:25142463 supporting_text: compound losses of wnt11r and fgf8a phenocopy tbx1 mutant pouch defects - *id026 - term: id: GO:0060041 label: retina development in camera-type eye evidence_type: IGI original_reference_id: PMID:15809038 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-080710-8 review: summary: Fgf8 and Fgf3 coordinate the onset of retinal differentiation. action: KEEP_AS_NON_CORE reason: Martinez-Morales et al. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - reference_id: PMID:15809038 supporting_text: The concerted activity of Fgf8 and Fgf3 is both necessary and sufficient to coordinate retinal differentiation independent of the connecting optic stalk. - term: id: GO:0060059 label: embryonic retina morphogenesis in camera-type eye evidence_type: IGI original_reference_id: PMID:19823566 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-070430-6 - ZFIN:ZDB-MRPHLNO-050818-6 review: summary: Fgf8/3/24 control nasal retina identity and eye morphogenesis. action: KEEP_AS_NON_CORE reason: Picker et al. 2009 (full text), triple mutant/morphant analysis. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - reference_id: PMID:19823566 supporting_text: Triple-mutant analysis shows that this combined Fgf signal fully controls nasal retina identity by regulating the nasal transcription factor Foxg1. - term: id: GO:0060271 label: cilium assembly evidence_type: IGI original_reference_id: PMID:23946439 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 - ZFIN:ZDB-MRPHLNO-131108-6 review: summary: ace interacts with 3-OST-5 in Kupffer's vesicle cilia length. action: KEEP_AS_NON_CORE reason: Neugebauer et al. (full text) place 3-OST-5 in the FGF pathway controlling KV cilia length. Cilium assembly is a downstream readout of Fgf8 signalling via ier2/fibp1 and foxj1a; fgf8a is not part of the ciliogenesis machinery. supported_by: - reference_id: PMID:23946439 supporting_text: 3-OST-5 functions in the fibroblast growth factor pathway to control cilia length via the ciliogenic transcription factors FoxJ1a and Rfx2. - &id047 reference_id: PMID:19164561 supporting_text: Cilia are also lost after suppression of FGF8, but can be rescued by injection of ier2 and fibp1 mRNA. - term: id: GO:0060271 label: cilium assembly evidence_type: IMP original_reference_id: PMID:19164561 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-041109-5 review: summary: Kupffer's vesicle cilia are lost after fgf8 knockdown. action: KEEP_AS_NON_CORE reason: 'Hong and Dawid (full text): loss of KV cilia after Fgf8 suppression, rescued by ier2 and fibp1. Upstream signalling role, not part of the assembly machinery.' supported_by: - *id047 - term: id: GO:0060788 label: ectodermal placode formation evidence_type: IMP original_reference_id: PMID:20885782 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-110214-2 review: summary: Fgf8 misexpression can induce preplacodal ectoderm. action: KEEP_AS_NON_CORE reason: Kwon et al. (full text). Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - reference_id: PMID:20885782 supporting_text: Localized ventral misexpression of Fgf8 and Chordin can activate ectopic preplacodal development anywhere within the zone of competence - term: id: GO:0061053 label: somite development evidence_type: IMP original_reference_id: PMID:9609821 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: summary: Somite development in ace mutants. action: KEEP_AS_NON_CORE reason: Reifers et al. 1998 describe fgf8 expression and requirements during somitogenesis. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - *id003 - term: id: GO:0061195 label: taste bud formation evidence_type: IMP original_reference_id: PMID:21791527 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-980202-822 review: summary: ace mutants have reduced taste buds. action: KEEP_AS_NON_CORE reason: Kapsimali et al. show compromised Fgf signalling reduces taste buds. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - reference_id: PMID:21791527 supporting_text: compromised Fgf signaling in the larva results in taste bud reduction and disorganization - term: id: GO:0061386 label: closure of optic fissure evidence_type: IGI original_reference_id: PMID:29625437 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-050714-1 - ZFIN:ZDB-MRPHLNO-180831-2 review: summary: 'Optic fissure closure: fgf8 is upregulated in adamts16 morphants (genetic interaction).' action: KEEP_AS_NON_CORE reason: Cao et al. show adamts16 restricts fgf8 in the optic cup; the IGI presumably records rescue by fgf8 knockdown. fgf8a here acts as a signal whose excess impairs closure. Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - reference_id: PMID:29625437 supporting_text: fibroblast growth factor 8 (fgf8) was ectopically upregulated in the OC - term: id: GO:0070121 label: Kupffer's vesicle development evidence_type: IMP original_reference_id: PMID:19164561 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-041109-5 review: summary: Kupffer's vesicle development requires Fgf8. action: ACCEPT reason: Hong and Dawid and Albertson and Yelick show that KV and its cilia depend on fgf8; this underlies the left-right role. supported_by: - *id047 - *id048 - term: id: GO:0071599 label: otic vesicle development evidence_type: IGI original_reference_id: PMID:24677486 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-101119-36 - ZFIN:ZDB-MRPHLNO-141230-19 - ZFIN:ZDB-MRPHLNO-141230-20 review: summary: Otic vesicle development in fgf8 mutants with fgf10b/fgf3 knockdown. action: KEEP_AS_NON_CORE reason: Maulding et al. (full text). Developmental phenotype readout of fgf8a loss (ace mutant, morpholino, or combined knockdown with another Fgf or pathway gene). fgf8a is a secreted FGFR ligand, so this is an acts_upstream_of_or_within role of the signal in a tissue that responds to it, not a core molecular activity. supported_by: - *id049 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:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: PMID:10595509 title: Development of noradrenergic neurons in the zebrafish hindbrain requires BMP, FGF8, and the homeodomain protein soulless/Phox2a. findings: [] - id: PMID:10603341 title: Induction and differentiation of the zebrafish heart requires fibroblast growth factor 8 (fgf8/acerebellar). findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract only. fgf8 required for induction of myocardial precursors; rescue by RNA and beads. - id: PMID:11802165 title: Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling. findings: [] - id: PMID:12591239 title: Wnt1 and wnt10b function redundantly at the zebrafish midbrain-hindbrain boundary. findings: [] - id: PMID:12642489 title: The role of the zebrafish nodal-related genes squint and cyclops in patterning of mesendoderm. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Abstract only. Nodal paper; fgf8 not mentioned in the abstract. - id: PMID:12835397 title: vhnf1 and Fgf signals synergize to specify rhombomere identity in the zebrafish hindbrain. findings: [] - id: PMID:12843251 title: Genetic analysis of the roles of Hh, FGF8, and nodal signaling during catecholaminergic system development in the zebrafish brain. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Full text. Includes the only direct redundancy test of fgf8a and fgf8b (ace;noi double mutants), negative for DA neurons. - id: PMID:12917294 title: Engrailed and Fgf8 act synergistically to maintain the boundary between diencephalon and mesencephalon. findings: [] - id: PMID:14651930 title: Interplay between FGF, one-eyed pinhead, and T-box transcription factors during zebrafish posterior development. findings: [] - id: PMID:14651935 title: Fgf signalling is required for formation of cartilage in the head. findings: [] - id: PMID:14660549 title: Isthmus-to-midbrain transformation in the absence of midbrain-hindbrain organizer activity. findings: [] - id: PMID:14711879 title: Nodal and Fgf pathways interact through a positive regulatory loop and synergize to maintain mesodermal cell populations. findings: [] - id: PMID:14745965 title: Early requirement for fgf8 function during hindbrain pattern formation in zebrafish. findings: [] - id: PMID:14757644 title: A direct role for Fgf but not Wnt in otic placode induction. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Abstract only. Supports fgf3/fgf8 in otic induction; the abstract describes Wnt8 upstream of Fgf, so the positive regulation of Wnt signaling annotation could not be verified. - id: PMID:15151985 title: Fgf signalling controls the dorsoventral patterning of the zebrafish embryo. findings: [] - id: PMID:15188428 title: Genetic interactions underlying otic placode induction and formation. findings: [] - id: PMID:15281067 title: Hedgehog and Fgf signaling pathways regulate the development of tphR-expressing serotonergic raphe neurons in zebrafish embryos. findings: [] - id: PMID:15342476 title: vhnf1 integrates global RA patterning and local FGF signals to direct posterior hindbrain development in zebrafish. findings: [] - id: PMID:15459102 title: Pax8 and Pax2a function synergistically in otic specification, downstream of the Foxi1 and Dlx3b transcription factors. findings: [] - id: PMID:15498491 title: Endocytosis controls spreading and effective signaling range of Fgf8 protein. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract only. Extracellular spreading and lysosomal clearance of tagged Fgf8. - id: PMID:15509770 title: An essential role for Fgfs in endodermal pouch formation influences later craniofacial skeletal patterning. findings: [] - id: PMID:15809038 title: Differentiation of the vertebrate retina is coordinated by an FGF signaling center. findings: [] - id: PMID:15932752 title: Roles for fgf8 signaling in left-right patterning of the visceral organs and craniofacial skeleton. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract only. fgf8 required for left-right asymmetry and Kupffer's vesicle. - id: PMID:16120642 title: Fgf8 drives myogenic progression of a novel lateral fast muscle fibre population in zebrafish. findings: [] - id: PMID:16236770 title: Fgf signals from a novel signaling center determine axial patterning of the prospective neural retina. findings: [] - id: PMID:16256099 title: Fgf19 regulated by Hh signaling is required for zebrafish forebrain development. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Abstract only. Fgf19 paper; the fgf3/fgf8 knockdown results behind the annotations are not in the abstract. - id: PMID:16611693 title: Differentiation of cerebellar cell identities in absence of Fgf signalling in zebrafish Otx morphants. findings: [] - id: PMID:16672336 title: Zebrafish endoderm formation is regulated by combinatorial Nodal, FGF and BMP signalling. findings: [] - id: PMID:16754885 title: Mutation of the atrophin2 gene in the zebrafish disrupts signaling by fibroblast growth factor during development of the inner ear. findings: [] - id: PMID:16873584 title: FGF signaling is required for {beta}-catenin-mediated induction of the zebrafish organizer. findings: [] - id: PMID:16890217 title: Noggin1 and Follistatin-like2 function redundantly to Chordin to antagonize BMP activity. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Abstract only. Noggin/follistatin-like paper; fgf8 not mentioned in the abstract. - id: PMID:16961592 title: Genomic organization, alternative splicing, and multiple regulatory regions of the zebrafish fgf8 gene. findings: [] - id: PMID:17026981 title: Fgf signaling negatively regulates Nodal-dependent endoderm induction in zebrafish. findings: [] - id: PMID:17215310 title: Specification of epibranchial placodes in zebrafish. findings: [] - id: PMID:17239227 title: Fgf-dependent otic induction requires competence provided by Foxi1 and Dlx3b. findings: [] - id: PMID:17448458 title: Fgf8 haploinsufficiency results in distinct craniofacial defects in adult zebrafish. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Full text. Describes the ace ti282a allele (splice-site mutation, frameshift, premature stop). - id: PMID:17522161 title: Changes in retinoic acid signaling alter otic patterning. findings: [] - id: PMID:17576618 title: REREa/Atrophin-2 interacts with histone deacetylase and Fgf8 signaling to regulate multiple processes of zebrafish development. findings: [] - id: PMID:17611226 title: Early developmental specification of the thyroid gland depends on han-expressing surrounding tissue and on FGF signals. findings: [] - id: PMID:18639539 title: Reiterative roles for FGF signaling in the establishment of size and proportion of the zebrafish heart. findings: [] - id: PMID:19164561 title: FGF-dependent left-right asymmetry patterning in zebrafish is mediated by Ier2 and Fibp1. findings: [] - id: PMID:19395641 title: Distinct phases of cardiomyocyte differentiation regulate growth of the zebrafish heart. findings: [] - id: PMID:19481538 title: Fgf4 is required for left-right patterning of visceral organs in zebrafish. findings: [] - id: PMID:19823566 title: Dynamic coupling of pattern formation and morphogenesis in the developing vertebrate retina. findings: [] - id: PMID:20885782 title: Identification of early requirements for preplacodal ectoderm and sensory organ development. findings: [] - id: PMID:21791527 title: Fgf signaling controls pharyngeal taste bud formation through miR-200 and Delta-Notch activity. findings: [] - id: PMID:22223680 title: Midbrain-hindbrain boundary patterning and morphogenesis are regulated by diverse grainy head-like 2-dependent pathways. findings: [] - id: PMID:23789101 title: Fgf22 regulated by Fgf3/Fgf8 signaling is required for zebrafish midbrain development. findings: [] - id: PMID:23946439 title: Differential roles for 3-OSTs in the regulation of cilia length and motility. findings: [] - id: PMID:24677486 title: Mesodermal Fgf10b cooperates with other fibroblast growth factors during induction of otic and epibranchial placodes in zebrafish. findings: [] - id: PMID:25142463 title: Tbx1 controls the morphogenesis of pharyngeal pouch epithelia through mesodermal Wnt11r and Fgf8a. findings: [] - id: PMID:27060628 title: An Fgf-Shh signaling hierarchy regulates early specification of the zebrafish skull. findings: [] - id: PMID:28493069 title: Comparison of molecular marker expression in early zebrafish brain development following chronic ethanol or morpholino treatment. findings: [] - id: PMID:29625437 title: Metalloproteinase Adamts16 Is Required for Proper Closure of the Optic Fissure. findings: [] - id: PMID:32345657 title: Fgf-driven Tbx protein activities directly induce myf5 and myod to initiate zebrafish myogenesis. findings: [] - id: PMID:9007239 title: Mutations in zebrafish genes affecting the formation of the boundary between midbrain and hindbrain. findings: [] - id: PMID:9609821 title: Fgf8 is mutated in zebrafish acerebellar (ace) mutants and is required for maintenance of midbrain-hindbrain boundary development and somitogenesis. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract only. Identifies acerebellar as the fgf8 (fgf8a) mutation; MHB organizer and cerebellum. - id: PMID:17708537 title: Duplication and divergence of fgf8 functions in teleost development and evolution. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract only. Establishes that zebrafish fgf8 and fgf17a are TGD co-orthologues of FGF8 (renamed fgf8a/fgf8b) and describes lineage-specific subfunction partitioning. - id: PMID:19562753 title: Evolution of developmental regulation in the vertebrate FgfD subfamily. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text. Synteny, expression and CNE comparison of FgfD genes in zebrafish and stickleback; main source for the expression partition between fgf8a and fgf8b. - id: PMID:19782672 title: Cis-regulation and chromosomal rearrangement of the fgf8 locus after the teleost/tetrapod split. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Abstract only. fgf8a enhancers are dispersed over the fbxw4 and slc2a15a bystander genes. - id: PMID:17387144 title: Genomic regulatory blocks encompass multiple neighboring genes and maintain conserved synteny in vertebrates. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Full text. The fgf8b (fgf17a) duplicate block has lost fbxw4, which carries fgf8 enhancers. - id: PMID:11091072 title: Overlapping and distinct functions provided by fgf17, a new zebrafish member of the Fgf8/17/18 subgroup of Fgfs. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract only. Original description of zebrafish fgf17 (= fgf8b); injection assay shows it acts like fgf8; its MHB expression is maintained by fgf8a. - id: PMID:28873404 title: Fibroblast growth factor signaling is required for early somatic gonad development in zebrafish. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Full text; used only for the statement that the fgf8 duplication is from the TGD. core_functions: - description: Secreted FGF8-subfamily ligand that binds FGF receptors and activates FGFR/Ras-MAPK signalling in receiving cells; its range is set by extracellular diffusion and endocytic clearance. molecular_function: id: GO:0005105 label: type 1 fibroblast growth factor receptor binding directly_involved_in: - id: GO:0008543 label: fibroblast growth factor receptor signaling pathway locations: - id: GO:0005576 label: extracellular region supported_by: - reference_id: PMID:15498491 supporting_text: If internalization is inhibited, Fgf8 protein accumulates extracellularly, spreads further, and activates target gene expression over a greater distance. - reference_id: PMID:11802165 supporting_text: Sef functions as a feedback-induced antagonist of Ras/Raf/MEK/MAPK-mediated FGF signalling. - description: Signal of the midbrain-hindbrain boundary (isthmic) organizer, required to maintain the MHB, midbrain identity and the cerebellum (acerebellar phenotype). molecular_function: id: GO:0008083 label: growth factor activity directly_involved_in: - id: GO:0030917 label: midbrain-hindbrain boundary development - id: GO:0021549 label: cerebellum development locations: - id: GO:0005576 label: extracellular region supported_by: - reference_id: PMID:9609821 supporting_text: Homozygous acerebellar embryos lack a cerebellum and the midbrain-hindbrain boundary organizer. - reference_id: PMID:14660549 supporting_text: cells of the isthmic and cerebellar primordia acquire a more rostral, tectal identity in the absence of the functional MHB organizer signal Fgf8 - description: Inductive signal for myocardial precursors (nkx2.5/gata4) and for otic placode induction (with fgf3); in zebrafish the cardiac role is carried by fgf8a alone. molecular_function: id: GO:0008083 label: growth factor activity directly_involved_in: - id: GO:0010002 label: cardioblast differentiation - id: GO:0043049 label: otic placode formation locations: - id: GO:0005576 label: extracellular region supported_by: - reference_id: PMID:10603341 supporting_text: These findings show that fgf8/acerebellar is required for induction and patterning of myocardial precursors. - reference_id: PMID:17522161 supporting_text: fgf8 mutants depleted of RA signaling produce few otic cells, and these cells fail to form a vesicle, indicating that Fgf8 is the primary factor responsible for otic induction in RA-depleted embryos - description: Required for Kupffer's vesicle formation and ciliogenesis, and hence for left-right asymmetry of brain, heart and gut. molecular_function: id: GO:0008083 label: growth factor activity directly_involved_in: - id: GO:0070121 label: Kupffer's vesicle development - id: GO:0007368 label: determination of left/right symmetry locations: - id: GO:0005576 label: extracellular region supported_by: - reference_id: PMID:15932752 supporting_text: We find that fgf8 is required for proper asymmetric development of the brain, heart and gut. - reference_id: PMID:19164561 supporting_text: Cilia are also lost after suppression of FGF8, but can be rescued by injection of ier2 and fibp1 mRNA. suggested_questions: - question: Does fgf8b expression rise in ace (ti282a, premature stop codon) mutants, as transcriptional adaptation would predict, and does it buffer shared domains such as the MHB and somites? - question: Would fgf8b coding sequence expressed from the fgf8a locus rescue ace, confirming that the two proteins are interchangeable in vivo? - question: What is the expression pattern of the single fgf8 gene of spotted gar, and does it include the heart, gastrula margin and telencephalon (fgf8a-only domains in zebrafish)? suggested_experiments: - hypothesis: fgf8a and fgf8b proteins are functionally equivalent; their differences are regulatory. description: Knock-in of fgf8b coding sequence into the fgf8a locus (or fgf8b mRNA injection into ace mutants) and scoring of MHB, heart and Kupffer's vesicle phenotypes. experiment_type: cross-rescue - hypothesis: fgf8a and fgf8b act redundantly in their shared domains (MHB, somites, otic vesicle). description: Compare ace single mutants with fgf8a;fgf8b double mutants, using a promoter-deletion (RNA-less) fgf8a allele to avoid transcriptional adaptation. experiment_type: double mutant analysis