Affinage

FGF8

Fibroblast growth factor 8 · UniProt P55075

Length
233 aa
Mass
26.5 kDa
Annotated
2026-06-09
100 papers in source corpus 45 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FGF8 is a secreted signaling ligand that functions as an organizer signal at multiple embryonic patterning centers, controlling cell survival, proliferation, migration, and fate specification across limb, brain, heart, ear, olfactory, and axial development (PMID:8548816, PMID:11101846, PMID:11101845, PMID:12736208, PMID:10603341). The gene produces a structurally complex family of secreted isoforms with distinct N-termini and different biological potencies, of which FGF8b is the most signaling-active form, selectively activating the Ras-ERK pathway to specify cerebellar fate, while the isoforms also differ in transforming potential (PMID:7768185, PMID:15294862, PMID:8891346). As an organizer ligand, FGF8 maintains the apical ectodermal ridge program required for limb outgrowth and Shh expression, with FGF4 acting redundantly to sustain limb mesenchyme survival (PMID:8548816, PMID:11101846, PMID:11101845, PMID:15328019); it is required for cell migration away from the primitive streak during gastrulation (PMID:10421635); and it maintains cell survival and patterning gene networks (Wnt1, Gbx2, En1/2, Otx2 repression) at the isthmic organizer governing midbrain/cerebellum formation (PMID:12736208, PMID:10518499). FGF8 acts both as a long-range diffusible morphogen forming graded fields in the neocortex and as a chemoattractant/chemokinetic cue directing cardiac neural crest and epithelial cell migration through FGFR1 and FGFR3 (PMID:21419761, PMID:20843859, PMID:26130757), with its spatial signaling range limited by receptor-mediated endocytosis and lysosomal clearance (PMID:15498491). In cardiogenesis, FGF8 acts as an inductive and autocrine signal that cooperates with BMP to drive cardiac marker expression and anterior heart field development (PMID:10603341, PMID:11934859, PMID:16720879). FGF8 transcription is tightly controlled: it is directly repressed by retinoic acid through a conserved RARE that recruits PRC2/H3K27me3 and the corepressors NCOR1/NCOR2, and is directly activated upstream by Pax2, Six1/Eya1, Tbx1, and Sp8/9 across distinct organizers (PMID:11704761, PMID:25053430, PMID:27506116, PMID:21364285, PMID:15358670). In disease contexts, FGF8 is an androgen receptor transcriptional target in prostate cancer, with AR binding androgen-responsive elements in its promoter (PMID:12140757), and FGF8b is oncogenic in transformation and tumorigenicity assays (PMID:8891346).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1995 High

    Established that FGF8 is not a single ligand but a structurally complex family of secreted isoforms with distinct N-termini, framing later findings that isoforms differ in potency and transforming activity.

    Evidence cDNA sequencing and splice-site identification of the mouse Fgf8 gene

    PMID:7768185

    Open questions at the time
    • Did not assign distinct biological functions to individual isoforms
    • Structural basis of receptor selectivity not addressed
  2. 1994 High

    Mapped FGF8 expression to multiple embryonic signaling centers, providing the spatial framework predicting roles in gastrulation, brain, limb, and facial morphogenesis.

    Evidence Whole-mount in situ hybridization and Northern blot across mouse embryogenesis

    PMID:7980556

    Open questions at the time
    • Expression alone did not establish causal function
    • Receptor and downstream pathway not identified
  3. 1996 High

    Showed FGF8 is sufficient and acts as an endogenous limb inducer, capable of substituting for the AER to maintain Shh and drive outgrowth, establishing it as an organizer ligand.

    Evidence FGF8 protein bead implantation and AER replacement in chick; in situ hybridization

    PMID:8548816 PMID:8674413

    Open questions at the time
    • Gain-of-function did not establish endogenous necessity
    • Receptor identity and signaling pathway not defined
  4. 1999 High

    Demonstrated FGF8 is essential for gastrulation, with FGF8/FGF4 signaling required for epiblast cells to migrate away from the primitive streak and form mesoderm/endoderm.

    Evidence Targeted Fgf8 disruption and compound mutant analysis with histology

    PMID:10421635

    Open questions at the time
    • Direct cellular mechanism of migration control not resolved
    • Receptor mediating the migration response not identified
  5. 2000 High

    Conditional inactivation in the AER established FGF8 as individually necessary for normal limb skeletal development, distinguishing it from other redundant AER-FGFs.

    Evidence Cre/loxP conditional inactivation in limb ectoderm; skeletal and gene expression analysis

    PMID:11101845 PMID:11101846

    Open questions at the time
    • Residual limb formation indicated compensating signals not yet defined
    • Quantitative dose-response not established
  6. 2004 High

    Resolved the redundancy problem by showing FGF4 compensates for FGF8 in the AER, with combined loss abolishing mesenchyme survival and Shh/Fgf10 expression to produce limbless mice.

    Evidence Compound conditional Fgf4/Fgf8 knockout; TUNEL; in situ hybridization

    PMID:15328019

    Open questions at the time
    • Did not define the receptor mediating survival signaling
    • Mechanism linking FGF signaling to Shh maintenance unresolved
  7. 2003 High

    Established that isthmic FGF8 maintains midbrain/cerebellum survival and patterning gene networks, defining its organizer function in the brain.

    Evidence Conditional Fgf8 inactivation in mes/met; gene expression and cell death assays

    PMID:12736208

    Open questions at the time
    • Did not separate survival from patterning functions mechanistically
    • Direct transcriptional targets not identified
  8. 2001 High

    Built the epistatic hierarchy at the isthmic organizer, placing En1/2 downstream and Gbx2 in regulatory loops with FGF8 for Otx2/Wnt1 control, and identified Pax2 as a necessary and sufficient upstream inducer of Fgf8.

    Evidence FGF8 bead treatment of explants; En1/2 and Gbx2 double mutants; Pax2 loss/gain-of-function; in situ hybridization

    PMID:10518499 PMID:11124114 PMID:11704761 PMID:9927596

    Open questions at the time
    • Direct vs indirect transcriptional regulation of targets not fully resolved
    • Whether FGF8 initiates or only maintains these patterns debated within these studies
  9. 2004 High

    Identified the Ras-ERK pathway and isoform-specific activity (FGF8b but not FGF8a) as the intracellular mechanism by which isthmic FGF8 specifies cerebellar fate.

    Evidence In ovo electroporation of dominant-negative Ras; ERK immunostaining; isoform-specific siRNA knockdown

    PMID:15294862

    Open questions at the time
    • Receptor coupling FGF8b to ERK in this context not identified
    • Structural basis of FGF8b vs FGF8a potency not addressed
  10. 2004 High

    Defined the mechanism limiting FGF8 signaling range, showing receptor-mediated endocytosis and lysosomal degradation set the effective morphogen spread.

    Evidence Live imaging of tagged Fgf8 in zebrafish; endocytosis inhibition; dominant-negative dynamin

    PMID:15498491

    Open questions at the time
    • Did not identify the receptor/clearance machinery components
    • Quantitative gradient parameters not modeled
  11. 2010 High

    Confirmed FGF8 acts as a classic long-range diffusible morphogen patterning neocortical area identity along the anteroposterior axis.

    Evidence FGF8 gradient immunofluorescence; fate mapping; dominant-negative receptor capture; ectopic source electroporation

    PMID:20843859

    Open questions at the time
    • Downstream transcriptional readout of the gradient not fully defined
    • Receptor distribution shaping the gradient not mapped
  12. 2011 High

    Showed FGF8 acts as a directional migratory cue, being chemotactic and chemokinetic for cardiac neural crest via FGFR1/FGFR3 and MAPK/ERK signaling.

    Evidence Transwell chemotaxis; dominant-negative FGFR1; FGFR3-blocking antibody; chimeras

    PMID:21419761

    Open questions at the time
    • Relative contributions of FGFR1 vs FGFR3 not separated
    • Mechanism distinguishing chemotaxis from chemokinesis unresolved
  13. 2007 High

    Identified FGFR3 as the receptor for FGF8 in cochlear cell-fate specification, where FGF8 induces pillar cell fate and inhibits outer hair cell fate.

    Evidence Conditional Fgf8 KO; FGFR3-blocking antibody; overexpression; cochlear explants

    PMID:17634195

    Open questions at the time
    • Downstream transcriptional effectors of the FGF8-FGFR3 axis not defined
    • Generalizability of FGFR3 use to other organizers not established
  14. 2000 High

    Established FGF8 as an inductive and cooperative signal in cardiogenesis, required for cardiac transcription factor expression and acting with BMP and autocrinely in the anterior heart field.

    Evidence Zebrafish fgf8 mutants with rescue; chick endoderm ablation/BMP co-application; mouse conditional KO

    PMID:10603341 PMID:11934859 PMID:16720879

    Open questions at the time
    • Direct vs indirect regulation of cardiac transcription factors not fully resolved
    • Receptor mediating cardiac response not identified
  15. 2005 High

    Extended FGF8 organizer roles to neural crest, otic, and olfactory development, defining redundancy with FGF3 in otic induction and parallel action with WNT in neural crest induction.

    Evidence Zebrafish fgf3/fgf8 mutants and morpholinos; Xenopus Msx1/Pax3 epistasis; conditional KO in anterior neural structures

    PMID:11437442 PMID:15691759 PMID:15741321 PMID:16267092

    Open questions at the time
    • Receptor selectivity across these tissues not defined
    • Direct transcriptional targets of FGF8 in neural crest not identified
  16. 2002 High

    Established multilayered transcriptional control of FGF8, with retinoic acid directly repressing it through a RARE recruiting PRC2/H3K27me3 and NCOR1/2 corepressors, and androgen receptor directly activating it via promoter androgen-responsive elements in prostate cancer.

    Evidence Transgenic RARE reporter mutagenesis and ChIP; CRISPR Ncor1/2 and RARE deletion; AR ChIP, reporter, and xenograft assays

    PMID:12054865 PMID:12140757 PMID:25053430 PMID:27506116

    Open questions at the time
    • Interplay between activating and repressing inputs at single loci not fully integrated
    • Tissue-specificity of these regulatory mechanisms not exhaustively mapped
  17. 2013 High

    Defined the genomic regulatory architecture of Fgf8 as a ~220 kb holo-enhancer landscape where enhancers act by chromosomal position, explaining how structural variation can misregulate the gene.

    Evidence Genomic engineering of the Fgf8 locus; reporter transgenes; 4C/Hi-C

    PMID:23453598

    Open questions at the time
    • Individual enhancer-to-tissue assignments not fully resolved
    • Link to human disease structural variants not established here
  18. 2011 High

    Placed FGF8 within upstream transcription factor pathways (Tbx1, Six1/Eya1, Sp8/9) governing cardiovascular, craniofacial, thyroid, and limb development, linking it to del22q11-type defects.

    Evidence Compound knockouts; ChIP/reporter showing direct Six1/Eya1 activation; conditional ablation and rescue in Tbx1 domain; Sp8/9 dominant-negative and morpholino

    PMID:15358670 PMID:19389367 PMID:21364285 PMID:28648799

    Open questions at the time
    • Combinatorial logic integrating these activators at the locus not resolved
    • Direct vs indirect regulation not established for all factors
  19. 2015 Medium

    Implicated FGF8 in tumor progression beyond prostate, acting through YAP1, HBXIP/CREB/miR-503, and PI3K/Akt/HIF1a-VEGF axes in colorectal and breast cancer.

    Evidence FGF8 over/knockdown in CRC and breast cancer cells; YAP1 siRNA; ChIP; miR-503 3'UTR reporter; angiogenesis and tumor models

    PMID:24464787 PMID:25473897

    Open questions at the time
    • Single-lab cell-line studies without independent confirmation
    • Receptor mediating oncogenic FGF8 signaling not defined in these contexts
  20. 1996 High

    Demonstrated isoform-specific oncogenicity, with FGF8b being the most transforming and tumorigenic isoform, connecting isoform structure to disease potential.

    Evidence NIH3T3 transformation assay; nude mouse tumorigenicity; chromosomal mapping

    PMID:8891346

    Open questions at the time
    • Molecular basis of differential transforming potency not resolved
    • Receptor and pathway driving transformation not identified here

Open questions

Synthesis pass · forward-looking unresolved questions
  • How distinct FGF8 isoforms achieve their different signaling potencies and receptor preferences at the structural and biochemical level, and how the combinatorial transcriptional inputs are integrated at the holo-enhancer landscape in a tissue-specific manner, remain unresolved.
  • No structural model linking isoform N-termini to receptor selectivity in the corpus
  • Integration of activating and repressing transcriptional inputs at the locus not mechanistically unified
  • Receptor identity not defined in several functional contexts

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0060089 molecular transducer activity 3
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1643685 Disease 3 R-HSA-162582 Signal Transduction 2
Partners
FGF4FGFR1FGFR3

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 The mouse Fgf8 gene uses multiple splice donor and acceptor sites to produce at least seven transcripts encoding a family of secreted FGF8 proteins with different N termini, making it the most structurally complex FGF family member described at that time. cDNA sequencing, identification of new coding exon and splice sites Development High 7768185
1994 FGF8 (originally identified as androgen-induced growth factor, AIGF) is expressed in the primitive streak, midbrain-hindbrain border, rostral forebrain, limb ectoderm/AER, nasal placode, and branchial arch ectoderm during mouse embryogenesis, consistent with roles in gastrulation, brain development, and limb/facial morphogenesis. Whole-mount in situ hybridization of E7.5–E14.5 mouse embryos; Northern blot Biochemical and Biophysical Research Communications High 7980556
1996 FGF8 protein applied to the flank of chick embryos induces additional limb formation, can replace the apical ectodermal ridge (AER) to maintain Shh expression, and promotes limb outgrowth and patterning; FGF8 is expressed in intermediate mesoderm and then in AER cells throughout limb development. FGF8 protein bead implantation into chick flank; AER replacement experiments; in situ hybridization Development High 8674413
1996 FGF8 in the intermediate mesoderm acts as an endogenous inducer of chick limb formation, initiates Fgf8 expression in the overlying ectoderm, promotes outgrowth and Shh expression in lateral plate mesoderm, and maintains mesoderm outgrowth in the established limb bud. FGF8 bead implantation; tissue ablation and replacement; in situ hybridization for Fgf8 and Shh Cell High 8548816
1999 Fgf8-null mouse embryos fail to express Fgf4 in the primitive streak; in the absence of both FGF8 and FGF4, epiblast cells undergo epithelial-to-mesenchymal transition but fail to migrate away from the streak, resulting in no embryonic mesoderm or endoderm. This identifies Fgf8 as essential for gastrulation and shows that FGF8/FGF4 signaling is required for cell migration away from the primitive streak. Targeted gene disruption (Fgf8−/−), compound mutant analysis, histology, in situ hybridization Genes & Development High 10421635
2000 Conditional inactivation of Fgf8 in the AER of mouse forelimb causes substantial reduction in limb-bud size, delay in Shh expression, misregulation of Fgf4, and hypoplasia or aplasia of specific skeletal elements, identifying Fgf8 as the only known AER-Fgf individually necessary for normal limb development. Conditional Cre/loxP gene inactivation in limb ectoderm; skeletal analysis; in situ hybridization for Shh, Fgf4 Nature Genetics High 11101845 11101846
2000 Conditional disruption of Fgf8 in mouse forelimb ectoderm reveals a requirement for Fgf8 in formation of the stylopod, anterior zeugopod, and autopod, and shows that loss of Fgf8 in the AER alters expression of Fgf4, Fgf9, Shh, and Bmp2. Conditional Cre/loxP gene disruption in forelimb; skeletal preparation; in situ hybridization Nature Genetics High 11101845
2004 Fgf4 compensates for loss of Fgf8 in the AER: mice lacking both Fgf4 and Fgf8 in the forelimb AER fail to maintain limb bud mesenchyme survival, showing prolonged apoptosis and near-complete abolition of Shh and Fgf10 expression, ultimately resulting in limbless mice when both genes are removed from all limb ectoderm. Compound conditional Cre/loxP knockout of Fgf4 and Fgf8; TUNEL apoptosis assay; in situ hybridization Developmental Biology High 15328019
2003 FGF8 signaling from the isthmic organizer is required for cell survival in the prospective midbrain and cerebellum; loss of Fgf8 in the mes/met causes failure to maintain Wnt1, Fgf17, Fgf18, and Gbx2 expression, followed by ectopic cell death and deletion of the midbrain and cerebellum. Conditional Fgf8 inactivation in mes/met; analysis of gene expression by in situ hybridization; cell death assays Development High 12736208
2001 In mouse brain explant cultures, FGF8b-soaked beads induce En2 and Gbx2 as the first responsive genes in diencephalic and midbrain tissue. Epistatic analysis using En1/2 double mutants and Gbx2 mutants shows: EN proteins are required downstream of FGF8 for Pax5 induction; GBX2 acts upstream of or parallel to FGF8 in repressing Otx2 and acts downstream of FGF8 to repress Wnt1. FGF8-soaked bead treatment of brain explants; double-mutant gene expression analysis; in situ hybridization Development High 11124114
2004 Endocytosis and subsequent lysosomal degradation ('restrictive clearance') limits the extracellular spreading and effective signaling range of Fgf8 protein in zebrafish neuroectoderm. Inhibiting endocytosis causes Fgf8 to accumulate extracellularly and expand its target gene expression domain; enhanced internalization shortens its signaling range. Live imaging of epitope-tagged Fgf8 in zebrafish; pharmacological inhibition of endocytosis; dominant-negative dynamin; target gene expression assays Current Biology High 15498491
1999 In chick, FGF8 is expressed asymmetrically on the right side of the node. FGF8 expression is induced by activin; FGF8 protein inhibits nodal and Pitx2 expression and induces cSnR, and left-sided FGF8 application randomizes heart looping, establishing FGF8 as a right-side determinant for left-right axis specification in chick. In situ hybridization; bead implantation of FGF8 protein; activin bead experiments; left-sided application of FGF8 protein Current Biology High 10074453
2002 In rabbit embryos (blastodisc topology), FGF8 acts as a right-side determinant: left-sided FGF8 application represses nodal and ectopic BMP4-induced nodal; right-sided inhibition of FGF8 signaling induces bilateral marker gene expression, showing FGF8 suppresses left-side identity from the right. FGF8 protein bead implantation; FGF8 inhibitor application; in situ hybridization for nodal, Pitx2 Current Biology Medium 12419180
2000 FGF8 acts as an inductive signal for zebrafish heart development: fgf8 is expressed in cardiac precursors and the ventricle; acerebellar (fgf8) mutants fail to express nkx2.5 and gata4 (but not gata6) in cardiac precursors; cardiac gene expression is rescued by fgf8 RNA injection or FGF8-coated bead implantation; pharmacological FGF inhibition phenocopies fgf8 mutant hearts. Zebrafish fgf8 mutant analysis; mRNA rescue injection; FGF8 bead implantation; pharmacological FGF receptor inhibition; in situ hybridization Development High 10603341
2002 In the avian embryo, Fgf8 expressed in endoderm adjacent to cardiac primordia is sufficient to rescue cardiac marker expression (Nkx2.5, Mef2c) after endoderm removal, and ectopic FGF8 induces cardiac markers only in regions with BMP signaling, demonstrating that FGF8 cooperates with BMP to regulate cardiogenesis. Endoderm ablation; FGF8 bead rescue; ectopic FGF8 bead implantation; BMP bead co-application; in situ hybridization and immunostaining Development High 11934859
2001 Zebrafish fgf3 and fgf8 function redundantly for otic placode induction: disruption of either alone gives moderate otocyst reduction; combined loss causes failure of pax8 and pax2.1 expression and ear loss. FGF signaling is required between 60% epiboly and tailbud stages; pax8 expression does not require FGF, placing pax8 upstream of Fgf3/Fgf8. Zebrafish fgf8 mutant (acerebellar); fgf3 morpholino knockdown; pharmacological FGF receptor inhibition; in situ hybridization Developmental Biology High 11437442 11959820 12385757
2005 In chick, endodermal Fgf8 is necessary and sufficient for Fgf19 expression in mesoderm; endoderm removal blocks otic induction, and Fgf8 acts upstream of the mesodermal FGF10 signal in the otic induction cascade. In mouse, Fgf8 hypomorphism combined with Fgf3 null leads to failure of otic induction and reduced mesodermal Fgf10 expression. FGF8 bead implantation; endoderm ablation; Fgf3/Fgf8 compound mutant mice; in situ hybridization Genes & Development High 15741321
2007 FGF8 secreted by inner hair cells signals through FGFR3 to induce pillar cell (PC) fate and inhibit outer hair cell (OHC) fate in the cochlear organ of Corti. Deletion of Fgf8 or blockade of Fgf8-Fgfr3 binding causes PC defects; overexpression of Fgf8 or ectopic FGFR3 activation induces ectopic PCs and inhibits OHC development. Conditional Fgf8 knockout; FGFR3-blocking antibody; Fgf8 overexpression; in vitro cochlear explant cultures; immunostaining Development High 17634195
2004 The Fgf8 signal in the cerebellum acts through activation of the Ras-ERK pathway: ERK is activated at the isthmus where Fgf8 is expressed; Fgf8b (but not Fgf8a or low-dose Fgf8b) activates ERK; dominant-negative Ras (RasS17N) converts metencephalic fate from cerebellum to tectum and cancels Fgf8b effects; siRNA knockdown of Fgf8b (not Fgf8a) extends Otx2 expression posteriorly. In ovo electroporation of dominant-negative Ras; ERK immunostaining; siRNA knockdown; in situ hybridization Development High 15294862
2001 Pax2 is necessary and sufficient to induce FGF8 expression at the mid/hindbrain boundary (MHB), in part through regulating Pax5/8 expression. A network of transcription factors (En1, Otx2, Gbx2, Grg4, Wnt1/4) established independently of Pax2 further refines the FGF8 expression domain through opposing effects on Pax2 activity. Loss-of-function Pax2 mutant mice; ectopic Pax2 expression; in situ hybridization for Fgf8 and related genes Nature Neuroscience High 11704761
1999 In avian embryo, FGF4 from notochord is required for En1 expression in neural plate; subsequently, En1 induces Fgf8 expression in the isthmus; FGF8 protein in anterior midbrain or posterior diencephalon repolarizes these tissues and can induce En1 and Pax2 expression (genes with earlier onset than Fgf8), suggesting FGF8 primarily maintains rather than initiates these expression patterns and also provides mitogenic stimulation. Tissue recombination explants; retroviral En1 overexpression; FGF8 bead implantation; in situ hybridization; BrdU proliferation assays Development High 9927596
1999 FGF8b-soaked beads induce the hindbrain gene Gbx2 and repress Otx2 in mouse midbrain explants; Wnt1-Fgf8b transgenic mice show ectopic En1, En2, Pax5, Gbx2 in hindbrain/spinal cord and transform midbrain/caudal forebrain toward anterior hindbrain fate through Gbx2 domain expansion and Otx2 repression. FGF8b bead treatment of mouse explants; Wnt1-Fgf8b transgenic mice; in situ hybridization for multiple patterning genes Development High 10518499
2014 Retinoic acid directly represses Fgf8 transcription through a conserved RARE (RA response element) upstream of Fgf8. Deletion of this RARE causes ectopic trunk Fgf8 expression. RA signaling recruits the repressive histone mark H3K27me3 and polycomb repressive complex 2 (PRC2) near the Fgf8 RARE in an RA-dependent manner, as shown by chromatin immunoprecipitation. Transgenic lacZ reporter with RARE deletion; ChIP for H3K27me3 and PRC2 in wild-type vs. Raldh2−/− embryos; in situ hybridization Development High 25053430
2016 Nuclear receptor corepressors NCOR1 and NCOR2 (SMRT) redundantly mediate RA-dependent repression of Fgf8. CRISPR/Cas9 Ncor1;Ncor2 double mutants exhibit increased Fgf8 expression and FGF signaling. ChIP shows NCOR1/2 (but not coactivators) are recruited to the Fgf8 RARE in an RA-dependent manner. Genomic deletion of the Fgf8 RARE partially derepresses Fgf8 caudally. CRISPR/Cas9 double knockout; chromatin immunoprecipitation; CRISPR/Cas9 RARE deletion; in situ hybridization and Western blot for FGF pathway activity Developmental Biology High 27506116
2002 In human prostate cancer, the androgen receptor (AR) directly regulates FGF8 transcription: AR and androgens increase FGF8b protein expression in vivo and in cell lines; the FGF8 promoter contains androgen-responsive elements; ChIP confirms in vivo AR binding to the FGF8 androgen-responsive promoter region; bicalutamide (anti-androgen) abolishes AR-mediated FGF8 induction. Luciferase reporter assays; ChIP; immunohistochemistry in CWR22 xenograft; AR transfection in AR-negative cells; androgen treatment/castration experiments Oncogene High 12140757
2002 An unliganded, phosphorylated (Ser77) RARα homodimer binds a novel two-half-site response element (separated by 87 nt) in the Fgf8 promoter; a canonical DR2-type RARE is bound by liganded RARα-RXRα heterodimer. These two elements mediate mutually exclusive transactivation leading to expression of different Fgf8 isoforms. Promoter cloning; luciferase reporter assays; EMSA; site-directed mutagenesis; transfection of phosphomimetic/mutant RARα Journal of Molecular Biology High 12054865
2005 In Xenopus, FGF8 induces neural crest through both Msx1 and Pax3 activities at the neural plate border; Msx1 acts upstream of Pax3 and ZicR1, which together activate Slug in a WNT-dependent manner. FGF8 and WNT signals thus act in parallel and converge on Pax3 during neural crest induction. Morpholino knockdown of Msx1 and Pax3; mRNA overexpression; dominant-negative constructs; in situ hybridization in Xenopus Developmental Cell High 15691759
2011 Six1 and Eya1 act upstream of Fgf8 in a Tbx1-Six1/Eya1-Fgf8 pathway regulating cardiovascular and craniofacial development; Six1/Eya1 directly activate Fgf8 as a downstream effector, and compound Six1;Eya1 mutants recapitulate del22q11 syndrome defects that are attributable in part to reduced Fgf8. Six1/Eya1 compound knockout mice; ChIP/reporter assays showing direct Fgf8 regulation by Six1/Eya1; genetic interaction with Tbx1 and Fgf8 Journal of Clinical Investigation High 21364285
2009 A Tbx1→Fgf8 pathway in pharyngeal mesoderm regulates early thyroid primordium size: Tbx1 regulates Fgf8 expression in mesoderm; conditional ablation of Fgf8 in Tbx1-expressing cells phenocopies the Tbx1 thyroid defect; re-expression of Fgf8 in the Tbx1 domain rescues the size defect in Tbx1 mutants. Conditional Cre-mediated Fgf8 ablation; Fgf8 cDNA rescue in Tbx1 domain; in situ hybridization; morphometric analysis Developmental Biology High 19389367
2011 FGF8 is chemotactic and chemokinetic for cardiac neural crest cells in vitro and in vivo: neural crest cells migrate toward FGF8 sources in transwell assays; the response is mediated by FGFR1 and FGFR3 and MAPK/ERK intracellular signaling; dominant-negative FGFR1 or FGFR3-blocking antibody slows neural crest migration in vivo. Neural crest explant migration assays; transwell chemotaxis assay; dominant-negative FGFR1 electroporation; FGFR3 function-blocking antibody; DiI labeling; quail-to-chick chimeras Developmental Biology High 21419761
2009 In zebrafish, fgf8 is required for asymmetric (leftward) migration of the parapineal nucleus; local provision of Fgf8 restores migration irrespective of source location; laterality bias toward left requires Nodal signaling acting in parallel with Fgf8, establishing Fgf8 as a regulator of neuroanatomical left-right asymmetry through control of bistable cell migration. fgf8 mutant (acerebellar) zebrafish analysis; local FGF8 protein provision; Nodal pathway manipulation; live imaging of parapineal migration Neuron High 19146810
2010 FGF8 functions as a classic diffusible morphogen in neocortex: FGF8 protein forms an A/P gradient by diffusing from an anterior source; cells outside the anterior telencephalon do not express Fgf8 (fate-mapping); a dominant-negative high-affinity FGF8 receptor captures endogenous FGF8 at a distance; reducing endogenous FGF8 in central neocortex shifts cells to a posterior area identity. FGF8 immunofluorescence gradient analysis; Fgf8-Cre fate mapping; dominant-negative FGF8 receptor electroporation; in utero electroporation of ectopic FGF8 sources Development High 20843859
2016 In axolotl limb regeneration, FGF8 (expressed in anterior blastema mesenchyme, maintained by SHH from posterior tissue) is necessary and sufficient (with endogenous HH signaling) to drive posterior-only blastemas to complete regeneration; SHH alone is insufficient in posterior-only blastemas, but FGF8 + SHH together are sufficient, revealing complementary cross-inductive signals. Blastema grafting; HH pathway activation; ectopic FGF8 expression; skeletal analysis; in situ hybridization Nature High 27120163
2013 The Fgf8 regulatory landscape spans ~220 kb containing multiple enhancer modules interspersed with unrelated genes that act as a coherent holo-enhancer unit: enhancers act on Fgf8 based on chromosomal position rather than promoter sequence, and structural variation within this domain can redirect enhancer activity. Genomic engineering (deletions and rearrangements) of the Fgf8 locus in mice; reporter transgene assays; 4C/Hi-C chromatin interaction analysis Developmental Cell High 23453598
2015 FGF8 induces nuclear localization of YAP1 and enhances transcription of YAP1 targets (CTGF, CYR61) in colorectal cancer cells; YAP1 knockdown blocks FGF8-induced cell growth, EMT, migration, and invasion, demonstrating that YAP1 is required for FGF8-mediated CRC growth and metastasis. FGF8 overexpression/knockdown in CRC cell lines; YAP1 nuclear localization assay; YAP1 siRNA knockdown; mouse tumor models; invasion and migration assays Oncotarget Medium 25473897
2014 HBXIP upregulates FGF8 by directly binding CREB to activate the FGF8 promoter in breast cancer cells, and independently through inhibition of miR-503 (which targets FGF8 3'UTR); FGF8 in turn upregulates VEGF through PI3K/Akt/HIF1α signaling, promoting tumor angiogenesis in a paracrine/autocrine manner. ChIP (HBXIP-CREB on FGF8 promoter); miR-503 luciferase 3'UTR assay; PI3K inhibitor experiments; matrigel angiogenesis assay; in vivo tumor models Carcinogenesis Medium 24464787
1996 Human FGF8 gene is located on chromosome 10q24; three alternatively spliced isoforms (FGF8a, FGF8b, FGF8e) differ at their N-termini; FGF8b is the most transforming isoform—transfection of NIH3T3 cells with FGF8b induces marked morphological transformation and strong tumorigenicity in nude mice, whereas FGF8a and FGF8e are moderately transforming. cDNA cloning; chromosomal mapping by FISH; NIH3T3 transformation assay; nude mouse tumorigenicity assay Cell Growth & Differentiation High 8891346
2015 In chick kidney (Wolffian duct) tubulogenesis, FGF8 acts as a chemoattractant on leader cells and prevents their epithelialization, while cells receiving less FGF8 (rear cells) undergo lumen formation. FGF8 acts as a binary switch distinguishing tubular elongation from epithelialization. FGF8 bead implantation; FGF signaling inhibition; live imaging of WD elongation; molecular markers for epithelialization Development Medium 26130757
2005 Fgf8 is expressed in the rim of the invaginating nasal pit and is required for olfactory epithelium neurogenesis and nasal cavity development; conditional inactivation of Fgf8 in anterior neural structures causes high apoptosis in the Fgf8 domain, loss of nasal cavity invagination, and elimination of virtually all OE neuronal types and the vomeronasal organ. Conditional Fgf8 knockout in anterior neural structures; TUNEL apoptosis assay; in situ hybridization for neural stem/progenitor markers; histology Development High 16267092
2000 Fgf8 and Fgf17 cooperate to regulate proliferation and differentiation of cerebellar vermis precursors: loss of Fgf17 decreases precursor proliferation in the vermis anlage after E11.5; loss of an additional copy of Fgf8 enhances and accelerates this phenotype; FGFs also regulate the polarized progression of differentiation in the vermis. Fgf17 null mice; compound Fgf17/Fgf8 heterozygotes; BrdU proliferation assay; in situ hybridization; behavioral analysis Development High 10751172
2006 Sp8 and Sp9 zinc-finger transcription factors are expressed in the AER and are ectodermal targets of Fgf10 signaling; they act as positive regulators of Fgf8 expression. Dominant-negative Sp8/Sp9 in chick and morpholino knockdown in zebrafish reduce Fgf8 expression and impair limb outgrowth; Wnt/β-catenin signaling positively regulates Sp8 (but not Sp9). Dominant-negative overexpression in chick; morpholino knockdown in zebrafish; Fgf8 in situ hybridization; genetic analysis in mouse Development High 15358670
2006 Autocrine Fgf8 signaling in cardiac crescent mesoderm is required for formation of the primary heart tube and addition of right ventricular/outflow tract myocardium; loss of Fgf8 in this domain decreases Erm expression and causes aberrant Isl1 and Mef2c production in the anterior heart field, linking Fgf8 signaling to transcription factor networks regulating anterior heart field survival/proliferation. Tissue-specific conditional Cre/loxP mutagenesis; in situ hybridization for Erm, Isl1, Mef2c; histological analysis of heart morphology Development High 16720879
2017 FGF8 expressed dynamically in the chick high-acuity area (HAA) anlage is regulated by retinoic acid-degrading enzymes; transient reduction of Fgf8 or manipulation of RA signaling disrupts HAA patterning including photoreceptor distribution, ganglion cell density, and interneuron organization. In situ hybridization; shRNA-mediated Fgf8 knockdown in chick retina; RA pathway manipulation; immunostaining of cell-type markers Developmental Cell Medium 28648799

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 The mouse Fgf8 gene encodes a family of polypeptides and is expressed in regions that direct outgrowth and patterning in the developing embryo. Development (Cambridge, England) 1049 7768185
1999 Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo. Genes & development 513 10421635
1996 Roles for FGF8 in the induction, initiation, and maintenance of chick limb development. Cell 508 8548816
2000 Fgf8 signalling from the AER is essential for normal limb development. Nature genetics 369 11101846
2002 Fgf8 is required for pharyngeal arch and cardiovascular development in the mouse. Development (Cambridge, England) 360 12223417
2006 Dose-dependent functions of Fgf8 in regulating telencephalic patterning centers. Development (Cambridge, England) 304 16613831
1996 Involvement of FGF-8 in initiation, outgrowth and patterning of the vertebrate limb. Development (Cambridge, England) 303 8674413
2005 Msx1 and Pax3 cooperate to mediate FGF8 and WNT signals during Xenopus neural crest induction. Developmental cell 267 15691759
2000 Fgf8 is required for outgrowth and patterning of the limbs. Nature genetics 264 11101845
2003 The isthmic organizer signal FGF8 is required for cell survival in the prospective midbrain and cerebellum. Development (Cambridge, England) 257 12736208
2000 Temporal and spatial gradients of Fgf8 and Fgf17 regulate proliferation and differentiation of midline cerebellar structures. Development (Cambridge, England) 222 10751172
2001 Coordinate expression of Fgf8, Otx2, Bmp4, and Shh in the rostral prosencephalon during development of the telencephalic and optic vesicles. Neuroscience 220 11734354
2000 Induction and differentiation of the zebrafish heart requires fibroblast growth factor 8 (fgf8/acerebellar). Development (Cambridge, England) 216 10603341
2001 Zebrafish fgf3 and fgf8 encode redundant functions required for otic placode induction. Developmental biology 211 11437442
2002 Fgf3 and Fgf8 are required together for formation of the otic placode and vesicle. Development (Cambridge, England) 202 11959820
2006 Required, tissue-specific roles for Fgf8 in outflow tract formation and remodeling. Development (Cambridge, England) 198 16720879
2002 Fgf8 and Fgf3 are required for zebrafish ear placode induction, maintenance and inner ear patterning. Mechanisms of development 187 12385757
1999 Sequential roles for Fgf4, En1 and Fgf8 in specification and regionalisation of the midbrain. Development (Cambridge, England) 181 9927596
1999 FGF8 can activate Gbx2 and transform regions of the rostral mouse brain into a hindbrain fate. Development (Cambridge, England) 175 10518499
2003 Zebrafish fgf24 functions with fgf8 to promote posterior mesodermal development. Development (Cambridge, England) 170 12925590
2000 Antagonistic signals between BMP4 and FGF8 define the expression of Pitx1 and Pitx2 in mouse tooth-forming anlage. Developmental biology 169 10625557
2002 Mouse GLI3 regulates Fgf8 expression and apoptosis in the developing neural tube, face, and limb bud. Developmental biology 167 12435361
2005 FGF8 initiates inner ear induction in chick and mouse. Genes & development 164 15741321
2002 Regulation of avian cardiogenesis by Fgf8 signaling. Development (Cambridge, England) 164 11934859
2004 The roles of Fgf4 and Fgf8 in limb bud initiation and outgrowth. Developmental biology 159 15328019
1994 Involvement of androgen-induced growth factor (FGF-8) gene in mouse embryogenesis and morphogenesis. Biochemical and biophysical research communications 159 7980556
2003 Dosage of Fgf8 determines whether cell survival is positively or negatively regulated in the developing forebrain. Proceedings of the National Academy of Sciences of the United States of America 152 12574514
2003 Loss of Bmp7 and Fgf8 signaling in Hoxa13-mutant mice causes hypospadia. Development (Cambridge, England) 145 12783783
2004 Sp8 and Sp9, two closely related buttonhead-like transcription factors, regulate Fgf8 expression and limb outgrowth in vertebrate embryos. Development (Cambridge, England) 137 15358670
2004 Reciprocal relationships between Fgf8 and neural crest cells in facial and forebrain development. Proceedings of the National Academy of Sciences of the United States of America 134 15041748
2001 EN and GBX2 play essential roles downstream of FGF8 in patterning the mouse mid/hindbrain region. Development (Cambridge, England) 133 11124114
2016 FGF8 and SHH substitute for anterior-posterior tissue interactions to induce limb regeneration. Nature 132 27120163
2005 Fgf8 expression defines a morphogenetic center required for olfactory neurogenesis and nasal cavity development in the mouse. Development (Cambridge, England) 131 16267092
2007 Fgf8 induces pillar cell fate and regulates cellular patterning in the mammalian cochlea. Development (Cambridge, England) 125 17634195
1999 FGF8 functions in the specification of the right body side of the chick. Current biology : CB 124 10074453
2001 Expression patterns of Fgf-8 during development and limb regeneration of the axolotl. Developmental dynamics : an official publication of the American Association of Anatomists 123 11146506
2013 An integrated holo-enhancer unit defines tissue and gene specificity of the Fgf8 regulatory landscape. Developmental cell 122 23453598
2003 Fgf3 and Fgf8 dependent and independent transcription factors are required for otic placode specification. Development (Cambridge, England) 122 12668634
1999 FGF8 over-expression in prostate cancer is associated with decreased patient survival and persists in androgen independent disease. Oncogene 122 10348350
2008 The complex genetics of Kallmann syndrome: KAL1, FGFR1, FGF8, PROKR2, PROK2, et al. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 118 18987492
2011 A Tbx1-Six1/Eya1-Fgf8 genetic pathway controls mammalian cardiovascular and craniofacial morphogenesis. The Journal of clinical investigation 113 21364285
2008 FGF15 promotes neurogenesis and opposes FGF8 function during neocortical development. Neural development 110 18625063
1999 Expression of chick Barx-1 and its differential regulation by FGF-8 and BMP signaling in the maxillary primordia. Developmental dynamics : an official publication of the American Association of Anatomists 107 10213385
2003 Unique and combinatorial functions of Fgf3 and Fgf8 during zebrafish forebrain development. Development (Cambridge, England) 106 12900450
2014 Retinoic acid controls body axis extension by directly repressing Fgf8 transcription. Development (Cambridge, England) 103 25053430
2001 Distinct regulators control the expression of the mid-hindbrain organizer signal FGF8. Nature neuroscience 100 11704761
2004 Endocytosis controls spreading and effective signaling range of Fgf8 protein. Current biology : CB 97 15498491
2012 Signaling by FGF4 and FGF8 is required for axial elongation of the mouse embryo. Developmental biology 96 22954964
2011 Novel FGF8 mutations associated with recessive holoprosencephaly, craniofacial defects, and hypothalamo-pituitary dysfunction. The Journal of clinical endocrinology and metabolism 96 21832120
2009 Role of mesodermal FGF8 and FGF10 overlaps in the development of the arterial pole of the heart and pharyngeal arch arteries. Circulation research 93 20035084
2008 Fgf8 controls regional identity in the developing thalamus. Development (Cambridge, England) 92 18653561
2010 FGF8 acts as a classic diffusible morphogen to pattern the neocortex. Development (Cambridge, England) 85 20843859
2004 FGF8-like1 and FGF8-like2 encode putative ligands of the FGF receptor Htl and are required for mesoderm migration in the Drosophila gastrula. Current biology : CB 85 15084280
2007 Differential requirements for FGF3, FGF8 and FGF10 during inner ear development. Developmental biology 82 17601531
2001 Neuroepithelial co-expression of Gbx2 and Otx2 precedes Fgf8 expression in the isthmic organizer. Mechanisms of development 82 11231064
2006 Lmx1b is essential for Fgf8 and Wnt1 expression in the isthmic organizer during tectum and cerebellum development in mice. Development (Cambridge, England) 80 17166916
2005 Retinoic acid activates myogenesis in vivo through Fgf8 signalling. Developmental biology 79 16316642
2008 Gli3 coordinates three-dimensional patterning and growth of the tectum and cerebellum by integrating Shh and Fgf8 signaling. Development (Cambridge, England) 78 18480159
1999 Fgf8 and Gbx2 induction concomitant with Otx2 repression is correlated with midbrain-hindbrain fate of caudal prosencephalon. Development (Cambridge, England) 76 10375509
2011 FGF8 signaling is chemotactic for cardiac neural crest cells. Developmental biology 75 21419761
2017 Fgf8 Expression and Degradation of Retinoic Acid Are Required for Patterning a High-Acuity Area in the Retina. Developmental cell 74 28648799
2002 Regulation of FGF8 expression by the androgen receptor in human prostate cancer. Oncogene 73 12140757
2009 An Fgf8-dependent bistable cell migratory event establishes CNS asymmetry. Neuron 70 19146810
2003 FGF8 isoform b expression in human prostate cancer. British journal of cancer 68 12778074
2004 The Fgf8 signal causes cerebellar differentiation by activating the Ras-ERK signaling pathway. Development (Cambridge, England) 64 15294862
2004 Induction and specification of midbrain dopaminergic cells: focus on SHH, FGF8, and TGF-beta. Cell and tissue research 64 15322912
2002 FGF8 acts as a right determinant during establishment of the left-right axis in the rabbit. Current biology : CB 61 12419180
2007 FGFR2, FGF8, FGF10 and BMP7 as candidate genes for hypospadias. European journal of human genetics : EJHG 60 17264867
2003 Engrailed and Fgf8 act synergistically to maintain the boundary between diencephalon and mesencephalon. Development (Cambridge, England) 60 12917294
2003 Sonic hedgehog and FGF8 collaborate to induce dopaminergic phenotypes in the Nurr1-overexpressing neural stem cell. Biochemical and biophysical research communications 59 12767935
1998 MMTV-Fgf8 transgenic mice develop mammary and salivary gland neoplasia and ovarian stromal hyperplasia. Oncogene 59 9840935
2002 Cloning of the mouse Sef gene and comparative analysis of its expression with Fgf8 and Spry2 during embryogenesis. Mechanisms of development 58 11960706
1996 Molecular cloning and characterization of human FGF8 alternative messenger RNA forms. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 58 8891346
2016 Fgf8 signaling for development of the midbrain and hindbrain. Development, growth & differentiation 55 27273073
2015 FGF8 promotes colorectal cancer growth and metastasis by activating YAP1. Oncotarget 55 25473897
2010 Nonsense mutations in FGF8 gene causing different degrees of human gonadotropin-releasing deficiency. The Journal of clinical endocrinology and metabolism 55 20463092
2001 Teneurin-2 is expressed in tissues that regulate limb and somite pattern formation and is induced in vitro and in situ by FGF8. Developmental dynamics : an official publication of the American Association of Anatomists 53 11146505
2009 The duration of Fgf8 isthmic organizer expression is key to patterning different tectal-isthmo-cerebellum structures. Development (Cambridge, England) 51 19793884
2013 Interaction between Foxc1 and Fgf8 during mammalian jaw patterning and in the pathogenesis of syngnathia. PLoS genetics 49 24385915
2009 Functional and phylogenetic analysis shows that Fgf8 is a marker of genital induction in mammals but is not required for external genital development. Development (Cambridge, England) 49 19592577
1999 aFGF immunoreactivity in prostate cancer and its co-localization with bFGF and FGF8. The Journal of pathology 49 10629559
2017 Mouse Fgf8-Cre-LacZ lineage analysis defines the territory of the postnatal mammalian isthmus. The Journal of comparative neurology 48 28510270
2014 The oncoprotein HBXIP enhances angiogenesis and growth of breast cancer through modulating FGF8 and VEGF. Carcinogenesis 48 24464787
2011 Gbx2 and Fgf8 are sequentially required for formation of the midbrain-hindbrain compartment boundary. Development (Cambridge, England) 47 21266408
2003 Ventral axial organs regulate expression of myotomal Fgf-8 that influences rib development. Developmental biology 45 12618132
2002 Promoter of FGF8 reveals a unique regulation by unliganded RARalpha. Journal of molecular biology 45 12054865
2016 Nuclear receptor corepressors Ncor1 and Ncor2 (Smrt) are required for retinoic acid-dependent repression of Fgf8 during somitogenesis. Developmental biology 44 27506116
2006 Fgf8 expression in the Tbx1 domain causes skeletal abnormalities and modifies the aortic arch but not the outflow tract phenotype of Tbx1 mutants. Developmental biology 41 16696966
2006 Cell aggregation-induced FGF8 elevation is essential for P19 cell neural differentiation. Molecular biology of the cell 40 16641368
2002 Spatial and temporal pattern of Fgf-8 expression during chicken development. Anatomy and embryology 38 11875659
1996 The human FGF-8 gene localizes on chromosome 10q24 and is subjected to induction by androgen in breast cancer cells. Oncogene 38 8700553
2018 FGF8 Signaling Alters the Osteogenic Cell Fate in the Hard Palate. Journal of dental research 35 29342370
2015 FGF8 coordinates tissue elongation and cell epithelialization during early kidney tubulogenesis. Development (Cambridge, England) 35 26130757
2012 The FGF8-related signals Pyramus and Thisbe promote pathfinding, substrate adhesion, and survival of migrating longitudinal gut muscle founder cells. Developmental biology 34 22609944
2005 FGF8, Wnt8 and Myf5 are target genes of Tbx6 during anteroposterior specification in Xenopus embryo. Developmental biology 34 16343478
2001 Sonic hedgehog and FGF8: inadequate signals for the differentiation of a dopamine phenotype in mouse and human neurons in culture. Experimental neurology 34 11312556
2009 Early thyroid development requires a Tbx1-Fgf8 pathway. Developmental biology 33 19389367
2007 Isolation, genomic structure and developmental expression of Fgf8 in the short-tailed fruit bat, Carollia perspicillata. The International journal of developmental biology 33 17554686
2004 Otx2, Gbx2, and Fgf8 expression patterns in the chick developing inner ear and their possible roles in otic specification and early innervation. Gene expression patterns : GEP 33 15465488
2015 Negative Fgf8-Bmp2 feed-back is regulated by miR-130 during early cardiac specification. Developmental biology 30 26165600

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