id: Q805B2 gene_symbol: fgf8b product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:7955 label: Danio rerio description: fgf8b is one of two zebrafish co-orthologues of vertebrate FGF8 retained from the teleost-specific genome duplication (the other is fgf8a). It was first described as zebrafish fgf17 (fgf17a). It encodes a secreted fibroblast growth factor of the FGF8/17/18 (FgfD) subfamily, with an N-terminal signal peptide and the FGF core domain, about 71% identical to fgf8a, and acts like fgf8a when misexpressed. Unlike fgf8a it is not expressed during gastrulation. It is first expressed at mid-somitogenesis in the ventral midbrain-hindbrain boundary and anterior somites, then in the optic stalks, otic vesicle, hyoid region and dorsal diencephalon. Its midbrain-hindbrain boundary expression depends on pax2a and is maintained by fgf8a. It is absent from the heart and from the fin bud, telencephalon and pharyngeal arches, where fgf8a is expressed. Its in vivo function has not been tested by loss of function; it is thought to act with fgf8a as an organizer signal at the midbrain-hindbrain boundary. existing_annotations: - term: id: GO:0005104 label: fibroblast growth factor receptor binding evidence_type: NAS original_reference_id: PMID:11091072 qualifier: enables review: summary: Binds FGF receptors (author statement, first description of zebrafish fgf17 = fgf8b). action: ACCEPT reason: fgf8b is a TGD co-orthologue of FGF8 with the FGF core domain, a signal peptide and 70.8% identity to fgf8a; injected fgf8b (then called fgf17) acts like fgf8. The ligand activity is therefore retained at the protein level and shared with fgf8a. The NAS is consistent with the more specific IBA FGFR1/FGFR2 binding rows. supported_by: - &id005 reference_id: PMID:11091072 supporting_text: Fgf8 and Fgf17 act as hierarchically organized signaling molecules during development of the MHB organizer and possibly other organizers in the developing nervous system - &id001 reference_id: PMID:11091072 supporting_text: fgf17 can act similar to fgf8 during gastrulation, when fgf17 is not normally expressed - 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 to type 1 FGF receptor (IBA, FGF8/17/18 node PTN007510376). action: ACCEPT reason: fgf8b lies inside the FgfD clade covered by the PAINT node, and there is no evidence of protein-level divergence. fgf8b is a TGD co-orthologue of FGF8 with the FGF core domain, a signal peptide and 70.8% identity to fgf8a; injected fgf8b (then called fgf17) acts like fgf8. The ligand activity is therefore retained at the protein level and shared with fgf8a. supported_by: - &id002 reference_id: PMID:17708537 supporting_text: the teleost genes called fgf8 and fgf17a are duplicates of the tetrapod gene Fgf8, and thus should be called fgf8a and fgf8b - *id001 - 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 to type 2 FGF receptor (IBA, FGF8/17/18 node PTN007510376). action: ACCEPT reason: fgf8b lies inside the FgfD clade covered by the PAINT node, and there is no evidence of protein-level divergence. fgf8b is a TGD co-orthologue of FGF8 with the FGF core domain, a signal peptide and 70.8% identity to fgf8a; injected fgf8b (then called fgf17) acts like fgf8. The ligand activity is therefore retained at the protein level and shared with fgf8a. supported_by: - *id002 - *id001 - 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: Active in the extracellular region (secreted ligand, IBA). action: ACCEPT reason: fgf8b has an N-terminal signal peptide, like fgf8a, whose extracellular spreading is directly shown (PMID:15498491). supported_by: - &id004 reference_id: file:DANRE/fgf8b/fgf8b-uniprot.txt record_section: ["FT:SIGNAL"] supporting_text: SIGNAL 1..27 - &id003 reference_id: file:DANRE/fgf8b/fgf8b-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: 'SUBCELLULAR LOCATION: Secreted' - 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. supported_by: - *id003 - *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: 'As for fgf8a and human FGF8: the node PTN000160075 covers intracellular FGFs as well as secreted ones, and fgf8b has a signal peptide and is a secreted ligand.' supported_by: - *id004 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 including intracellular and non-classically secreted FGFs; fgf8b has a signal peptide. - term: id: GO:0007389 label: pattern specification process evidence_type: NAS original_reference_id: PMID:11091072 qualifier: involved_in review: summary: Pattern specification process (author statement). action: KEEP_AS_NON_CORE reason: Reifers et al. propose that Fgf8 and Fgf17 (= fgf8b) act hierarchically in the MHB organizer and possibly other neural organizers. The statement rests on expression and gain of function, not on loss of fgf8b function, which has not been published. Broad and non-core. supported_by: - *id005 - 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: MARK_AS_OVER_ANNOTATED reason: The fgf8a evidence behind this kind of rule is gastrula-stage mesoderm formation (ace;oep interactions). fgf8b is not expressed during gastrulation and has no loss-of-function data; its somite expression begins at the 8-somite stage. The inference is not supported for fgf8b. Its paralogue fgf8a keeps this term. supported_by: - &id006 reference_id: file:DANRE/fgf8b/fgf8b-uniprot.txt record_section: ["CC:DEVELOPMENTAL STAGE"] supporting_text: Not expressed during gastrulation. - 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 (IBA). action: ACCEPT reason: fgf8b is a TGD co-orthologue of FGF8 with the FGF core domain, a signal peptide and 70.8% identity to fgf8a; injected fgf8b (then called fgf17) acts like fgf8. The ligand activity is therefore retained at the protein level and shared with fgf8a. supported_by: - *id001 - 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: fgf8b is a TGD co-orthologue of FGF8 with the FGF core domain, a signal peptide and 70.8% identity to fgf8a; injected fgf8b (then called fgf17) acts like fgf8. The ligand activity is therefore retained at the protein level and shared with fgf8a. supported_by: - *id001 - 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 (IBA). action: KEEP_AS_NON_CORE reason: Generic FGF mitogenic role; no fgf8b-specific data. Kept as non-core, as for fgf8a and human FGF8. supported_by: - *id001 - 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 pathway for an FGF ligand; protein-level activity is retained (injection assay). supported_by: - *id001 - term: id: GO:0008543 label: fibroblast growth factor receptor signaling pathway evidence_type: NAS original_reference_id: PMID:11091072 qualifier: involved_in review: summary: FGF receptor signaling pathway (author statement). action: ACCEPT reason: Consistent with the IBA. supported_by: - *id005 - 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: MARK_AS_OVER_ANNOTATED reason: No fgf8b-specific evidence. The fgf8a data for this term are from gastrula and early neural plate patterning, before fgf8b is expressed. supported_by: - *id006 - 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 PTN002608342). action: MARK_AS_OVER_ANNOTATED reason: 'The PAINT node is sound: zebrafish fgf8a, fgf24 and mouse Fgf8 act in D/V patterning, and fgf8b protein can act like fgf8 when injected during gastrulation. But the embryonic D/V axis is set in the blastula and gastrula, when fgf8b is not expressed; the in vivo role is carried by fgf8a (PMID:15151985). This is an expression-level loss of an ancestral subfunction in one copy, which IBA propagation cannot see. fgf8a keeps the term.' supported_by: - *id006 - *id001 - reference_id: PMID:15151985 supporting_text: we show that loss of Fgf8 function enhances the ventralisation of chordin-deficient embryos propagation_review: root_cause: PROPAGATION_BAD failure_modes: - CONTEXT_OR_TISSUE_MISMATCH source_entities: - source_id: PANTHER:PTN002608342 source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET comment: Node is supported by fgf8a, fgf24 and mouse Fgf8; fgf8b retains protein activity but is not expressed at the stages when the D/V axis is patterned. - 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 (IBA). action: KEEP_AS_NON_CORE reason: Plausible from expression at the MHB and in the dorsal diencephalon, but broad and without fgf8b-specific data. Non-core. supported_by: - &id007 reference_id: PMID:19562753 supporting_text: with strong expression of both genes in both species in the midbrain-hindbrain border (MBH) and somites (Fig. 6A–H) - 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 (IBA). action: KEEP_AS_NON_CORE reason: Generic FGF-family role; no fgf8b-specific data. Non-core. supported_by: - *id001 - term: id: GO:0030917 label: midbrain-hindbrain boundary development evidence_type: NAS original_reference_id: PMID:11091072 qualifier: involved_in review: summary: Midbrain-hindbrain boundary development (author statement). action: KEEP_AS_NON_CORE reason: 'fgf8b is expressed in the MHB, where its maintenance depends on fgf8a and its expression on pax2a dose; the authors propose a hierarchical role with fgf8a. No loss-of-function test exists, and the only double-loss experiment (ace;noi, lacking both) was scored for dopaminergic neurons only (PMID:12843251). Kept as non-core: plausible and consistent with the shared MHB domain, but not demonstrated.' supported_by: - reference_id: PMID:11091072 supporting_text: only maintenance of fgf17 expression is disturbed at the MHB of acerebellar/fgf8 mutants - reference_id: PMID:11091072 supporting_text: Analysis of zebrafish MHB mutants demonstrates a gene-dosage dependent requirement of fgf17 expression for the no isthmus// pax2.1 gene - *id007 - 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: REMOVE reason: 'This is a blastula/gastrula process: FGF/ERK signalling limits Nodal-induced endoderm progenitors (PMID:16672336), a role of fgf8a. fgf8b is not expressed during gastrulation and there is no evidence that it acts in endoderm specification. The machine inference should not be carried to fgf8b.' supported_by: - *id006 - 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: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: Canonical output of FGF ligand signalling; protein activity is retained. supported_by: - *id001 references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - 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. First description of zebrafish fgf17, now fgf8b: expression, injection assay, regulation by pax2a and fgf8a.' - 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. Renames fgf17a as fgf8b (TGD co-orthologue of FGF8); 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. Expression and CNE comparison of fgf8a and fgf8b in zebrafish and stickleback. - 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 duplicate block lost fbxw4, a carrier of fgf8 enhancers. - 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. ace;noi double mutants lacking fgf8a function and fgf8b (FGF17) expression: no enhanced DA-neuron phenotype.' - id: PMID:15151985 title: Fgf signalling controls the dorsoventral patterning of the zebrafish embryo. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Abstract only. fgf8a (not fgf8b) role in gastrula D/V patterning; cited to explain the D/V IBA decision. - id: PMID:16672336 title: Zebrafish endoderm formation is regulated by combinatorial Nodal, FGF and BMP signalling. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Abstract only. FGF/ERK restriction of endoderm progenitors at gastrula stage (fgf8a); cited for the ARBA REMOVE. - id: PMID:15498491 title: Endocytosis controls spreading and effective signaling range of Fgf8 protein. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Abstract only. Extracellular spreading of zebrafish Fgf8a protein; cited by analogy for the secreted location. core_functions: - description: Secreted FGF8-subfamily ligand for FGF receptors that activates FGFR/MAPK signalling; protein activity equivalent to fgf8a in an injection assay. Its in vivo roles are confined to post-gastrula domains shared with fgf8a (MHB, somites, otic vesicle). 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: - *id001 - *id002 suggested_questions: - question: Does fgf8b have any in vivo function on its own? No fgf8b mutant or morphant phenotype has been published. - question: Is fgf8b upregulated in ace (premature-stop) mutants, and does it contribute to the residual MHB and somite signalling there? suggested_experiments: - hypothesis: fgf8b is dispensable alone but acts redundantly with fgf8a at the MHB and in somites. description: Generate fgf8b null alleles (including a promoter-deletion, RNA-less allele) and analyse single mutants and fgf8a;fgf8b double mutants for MHB, cerebellum, somite muscle and otic phenotypes. experiment_type: double mutant analysis