Affinage

FOXD3

Forkhead box protein D3 · UniProt Q9UJU5

Length
478 aa
Mass
47.6 kDa
Annotated
2026-06-09
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FOXD3 is a forkhead/winged-helix transcription factor that acts predominantly as a context-dependent transcriptional repressor to maintain progenitor and pluripotent states and to restrict premature differentiation (PMID:12381664, PMID:18653770, PMID:17092955). In the early embryo it is required cell-autonomously for maintenance of pluripotent epiblast and for embryonic stem cell self-renewal and survival, functioning independently of Oct4, Sox2, and Nanog to suppress differentiation programs (PMID:12381664, PMID:18653770). At the chromatin level FOXD3 operates as a dual-function enhancer regulator, recruiting the SWI/SNF ATPase BRG1 to open nucleosomes while simultaneously recruiting HDAC1/2 to limit enhancer activation, and during the transition from naive to primed pluripotency it decommissions naive and germline enhancers, after which FOXD3 must itself be silenced to license primordial germ cell specification (PMID:26748757, PMID:26748758). FOXD3 is a core regulator of neural crest specification and multipotency: it is induced at the neural crest locus by CHD7/Oct3/4/Sox2/Nanog in a BMP/Wnt-dependent manner and through Pax7/Msx1-2/Ets1 and Zic1 enhancer inputs, acts jointly with tfap2a for neural crest induction, and lies genetically upstream of Slug, snai1b, and sox10 to maintain neural potential and survival while repressing mesenchymal and pigment-cell fates (PMID:11493569, PMID:16499899, PMID:21228004, PMID:21963426, PMID:23284303, PMID:27579714). It directly represses the mitfa promoter to govern the melanophore-versus-iridophore and melanocyte-versus-Schwann-cell fate decisions (PMID:18068699, PMID:20460180, PMID:23858437), and acts non-cell-autonomously in the Xenopus organizer to induce Nodal-related signals and dorsal mesoderm (PMID:17092955). In cancer, FOXD3 is re-induced upon attenuation of mutant B-RAF/MEK signaling in melanoma, where it drives p53/p21-dependent G1 arrest, represses the Rnd3-RhoA-ROCK migration axis through direct promoter binding, and confers tolerance to BRAF/MEK inhibitors (PMID:20332228, PMID:21996740, PMID:21478267); across other carcinomas it functions as a tumor suppressor through direct promoter activation of targets such as NDRG1, miR-137, and miR-214 and repression of EGFR-Ras-MEK-ERK signaling (PMID:24269992, PMID:24970808, PMID:27811858, PMID:27926503).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1998 Medium

    Established where FOXD3 acts in the embryo by mapping its expression to premigratory/migrating neural crest and motor neuron progenitors, framing it as a candidate neural crest regulator.

    Evidence In situ hybridization and linkage mapping in mouse embryo

    PMID:9767163

    Open questions at the time
    • Expression alone does not establish function
    • No direct targets or binding sites defined
  2. 2001 High

    Demonstrated FOXD3 is necessary and sufficient for neural crest determination and acts upstream of Slug, defining its position in the neural crest gene regulatory hierarchy.

    Evidence Xenopus gain/loss-of-function, dominant-negative construct, and Slug rescue epistasis

    PMID:11493569

    Open questions at the time
    • Direct DNA targets not identified
    • Molecular mechanism of repression vs activation not resolved
  3. 2002 High

    Showed FOXD3 is required cell-autonomously for pluripotent epiblast maintenance, separating its role from initiation of the Oct4/Sox2 pluripotency program.

    Evidence Germline knockout mouse with chimera analysis and blastocyst culture

    PMID:12381664

    Open questions at the time
    • Downstream effectors of survival/self-renewal unknown
    • Mechanism of repression at chromatin not addressed
  4. 2006 High

    Defined FOXD3 as a transcriptional repressor that non-cell-autonomously induces mesoderm via Nodal-related signals, and as a direct transactivator of myf5, revealing context-dependent activator/repressor behavior.

    Evidence Xenopus repressor/activator fusion constructs with Nodal-inhibitor rescue; yeast one-hybrid plus luciferase and zebrafish morpholino epistasis for myf5

    PMID:16386728 PMID:17092955

    Open questions at the time
    • Co-factors mediating repressor vs activator switch not identified
    • Direct Nodal-related target promoters not mapped
  5. 2006 High

    Placed foxd3 upstream of snai1b and sox10 in neural crest specification while showing fate-selective requirement (neuronal/glial/cartilage but not melanocyte), refining its lineage-specific roles.

    Evidence Zebrafish forward-genetic sym1 mutant with expression analysis and TUNEL

    PMID:16499899

    Open questions at the time
    • Direct vs indirect regulation of snai1b/sox10 not distinguished
    • Cause of lineage-selective apoptosis unresolved
  6. 2007 High

    Identified mitfa as a direct repression target and embedded FOXD3 in an HDAC1→Foxd3⊣Mitfa pathway controlling melanogenesis.

    Evidence Zebrafish hdac1 mutant with foxd3 morpholino rescue and chromatin association at the mitfa promoter

    PMID:18068699

    Open questions at the time
    • Co-repressor complex at mitfa promoter not defined
    • Mechanism of HDAC1 repression of foxd3 not detailed
  7. 2008 High

    Distinguished FOXD3's ESC self-renewal/survival function from the core pluripotency factors, showing it represses differentiation and promotes survival independently of Oct4/Sox2/Nanog.

    Evidence Tamoxifen-inducible conditional knockout in ESCs with apoptosis, clonal self-renewal, and lineage marker assays

    PMID:18653770

    Open questions at the time
    • Direct survival/differentiation target genes not yet identified
    • Chromatin mechanism not addressed
  8. 2009 Medium

    Positioned Disc1 upstream of foxd3/sox10 in cranial neural crest migration, extending the regulatory inputs controlling FOXD3 levels.

    Evidence Zebrafish disc1 morpholino with live migration imaging and in situ hybridization

    PMID:19570850

    Open questions at the time
    • Direct vs indirect repression of foxd3 by Disc1 not shown
    • Single-lab morpholino approach
  9. 2010 High

    Established FOXD3 re-expression as a tumor-suppressive output of B-RAF/MEK inhibition in melanoma, causing p53/p21-dependent G1 arrest.

    Evidence siRNA, ectopic expression, MEK inhibitor treatment, and p53/p21 depletion rescue in mutant B-RAF melanoma cells

    PMID:20332228

    Open questions at the time
    • Direct FOXD3 targets driving p21 induction not mapped
    • How B-RAF/MEK suppresses FOXD3 not resolved
  10. 2010 High

    Defined a Foxd3/Mitfa transcriptional switch governing the bi-potent melanophore/iridophore fate decision from a common mitfa+ precursor.

    Evidence Zebrafish single/double mutant epistasis with photoconvertible EosFP lineage tracing

    PMID:20460180

    Open questions at the time
    • Direct iridophore-program targets beyond pnp4a not defined
    • Cofactors for fate switch unknown
  11. 2011 High

    Showed Foxd3 maintains cell-intrinsic neural crest multipotency by repressing mesenchymal/skeletal fates, and dissected its anti-migratory mechanism via direct repression of Rnd3-RhoA-ROCK in melanoma.

    Evidence Conditional NC-specific KO with clonal fate assays (mouse); ChIP at Rnd3 promoter with ROCK-inhibitor rescue (melanoma)

    PMID:21228004 PMID:21478267

    Open questions at the time
    • Direct mesenchymal-repression targets in NC not fully mapped
    • Rnd3 work is single-lab Medium-confidence
  12. 2011 High

    Demonstrated tfap2a and foxd3 are jointly necessary and sufficient for neural crest induction via modulation of Bmp/Wnt signaling, and that FOXD3 upregulation confers BRAF-inhibitor tolerance in melanoma.

    Evidence Zebrafish double-mutant analysis with pathway readouts; siRNA/overexpression with PLX4032/4720 cell-death assays in melanoma

    PMID:21963426 PMID:21996740

    Open questions at the time
    • Mechanism by which FOXD3 promotes drug tolerance not defined
    • Direct Bmp/Wnt-pathway targets unknown
  13. 2011 High

    Showed Foxd3 and Pax3 cooperate in a dosage-sensitive manner for cardiac neural crest progenitor survival, defining a genetic partnership.

    Evidence Compound conditional Foxd3 KO with Pax3 heterozygosity, histology and apoptosis assays in mouse

    PMID:21254333

    Open questions at the time
    • Molecular basis of Foxd3-Pax3 cooperation (physical vs genetic) not established
    • Shared survival target genes unknown
  14. 2012 High

    Mapped the upstream enhancer logic controlling FoxD3 across neural crest subpopulations, showing distinct Pax7/Msx1-2/Ets1 (cranial NC1) and Zic1 (vagal/trunk NC2) inputs.

    Evidence Enhancer reporters, mutational analysis, in vivo ChIP, and morpholino epistasis in chick/Xenopus

    PMID:23284303

    Open questions at the time
    • How distinct enhancer usage maps to functional output not resolved
    • FOXD3's own targets in these subpopulations not addressed
  15. 2013 High

    Demonstrated Foxd3 controls melanocyte-vs-Schwann-cell and neuron-vs-glia fate switches, and acts as a context-dependent tumor suppressor in neuroblastoma via direct NDRG1 activation.

    Evidence Avian/mouse gain- and loss-of-function with lineage tracing; luciferase, ChIP, knockdown, and xenograft with NDRG1 rescue in neuroblastoma

    PMID:23858437 PMID:24269992 PMID:24270162

    Open questions at the time
    • Direct binding for many ESC microarray targets unconfirmed
    • NDRG1 work single-lab Medium-confidence
  16. 2016 High

    Resolved the chromatin mechanism: FOXD3 dually recruits BRG1 (enhancer opening) and HDAC1/2 (activation restraint), and decommissions naive/germline enhancers to drive exit from naive pluripotency before being silenced for PGC specification.

    Evidence ChIP-seq, ATAC-seq, co-IP for BRG1 and HDAC1/2, RNA-seq, and conditional KO in ESCs and EpiSCs

    PMID:26748757 PMID:26748758

    Open questions at the time
    • What dictates priming vs silencing at a given enhancer not fully defined
    • Determinants of ESC vs EpiSC binding-site selection unknown
  17. 2016 Medium

    Mapped the regulatory network controlling and downstream of FoxD3 in neural crest stem cell formation, with CHD7/Oct3/4/Sox2/Nanog inducing FoxD3 in a BMP/Wnt-dependent manner and FoxD3 promoting Sox10.

    Evidence ChIP at FoxD3 regulatory regions, siRNA knockdown, and histone methyltransferase inhibition

    PMID:27579714

    Open questions at the time
    • Direct FoxD3 occupancy at Sox10 not shown here
    • Single-lab study
  18. 2017 Medium

    Extended FOXD3's tumor-suppressive repressor role to direct activation of miR-137 (AKT2/mTOR) and miR-214 (MED19) and suppression of EGFR-Ras-MEK-ERK in carcinomas.

    Evidence ChIP/luciferase, knockdown/overexpression, EGFR inhibitor rescue, and xenografts in HCC, CRC, and colon cancer

    PMID:24970808 PMID:27811858 PMID:27926503

    Open questions at the time
    • Each axis established in a single lab/cancer type
    • Whether these reflect a unified mechanism vs context-specific outputs unclear
  19. 2020 Medium

    Linked FOXD3 to immune evasion by showing it regulates VISTA expression, with BRAF inhibition raising FOXD3 and lowering VISTA.

    Evidence siRNA, BRAF inhibitor treatment, in vivo tumor growth, and flow cytometry of immune infiltrate in melanoma

    PMID:31940493

    Open questions at the time
    • Direct FOXD3 binding at the VISTA promoter not demonstrated
    • Single-lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how a single forkhead factor selects between repressing, priming, and activating distinct enhancers/promoters across pluripotency, neural crest, and cancer contexts, and which cofactors dictate this switch genome-wide.
  • No unified model of cofactor-determined activator/repressor switching
  • Determinants of cell-type-specific binding-site selection unresolved
  • Direct human disease-causing mutation not identified in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 6 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-1643685 Disease 6 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-4839726 Chromatin organization 2 R-HSA-1640170 Cell Cycle 1
Partners
BRG1HDAC1HDAC2PAX3TFAP2A

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Foxd3 is required for maintenance of pluripotent epiblast cells in the early mouse embryo. Foxd3-/- embryos die after implantation (~E6.5) with loss of epiblast cells and expansion of extraembryonic tissues. Foxd3-/- blastocysts express Oct4, Sox2, and Fgf4 normally but inner cell mass fails to expand in vitro, and Foxd3-/- ES cell lines cannot be established. Chimera analysis shows Foxd3 function is required cell-autonomously in the epiblast. Germline knockout mouse, chimera analysis, in vitro blastocyst culture, immunofluorescence for pluripotency markers Genes & development High 12381664
2001 FoxD3 is required for neural crest determination in Xenopus. Overexpression of FoxD3 in ectoderm induces neural crest markers, while a dominant-negative FoxD3 (FoxD3delN) inhibits neural crest differentiation without suppressing CNS marker Sox2. Loss-of-function phenotypes are rescued by co-injection of Slug. FoxD3 is epistatic upstream of Slug: Slug induction by Zic factors requires FoxD3-related signaling. Xenopus overexpression, dominant-negative construct (FoxD3delN), morpholino epistasis, animal cap explant assays Development (Cambridge, England) High 11493569
1998 Hfh2 (FOXD3) is expressed in premigratory and migrating neural crest cells in the early mouse embryo and in motor neuron progenitors of the developing spinal cord, as determined by in situ hybridization. The Hfh2 gene was mapped to mouse chromosome 4 by linkage analysis. In situ hybridization, linkage analysis Mechanisms of development Medium 9767163
2006 Zebrafish foxd3 (sym1 allele with disrupted forkhead DNA-binding domain) is selectively required for neural crest specification toward neuronal, glial, and cartilage fates but not melanocytes. sym1 mutants have normal numbers of premigratory neural crest cells but reduced snai1b and sox10 expression, implicating foxd3 as an upstream regulator of these transcription factors. Neural crest migration onset is delayed, migratory trunk neural crest cells are reduced, and TUNEL analysis reveals aberrant apoptosis in hindbrain neural crest. Zebrafish forward genetics (sym1 mutant), gene expression analysis, TUNEL apoptosis assay Developmental biology High 16499899
2008 Foxd3 is required for self-renewal and pluripotency maintenance in mouse embryonic stem cells (ESCs). Conditional deletion of Foxd3 in ESCs causes increased apoptosis, decreased clonal self-renewal, and precocious differentiation along trophectoderm, endoderm, and mesendoderm lineages, despite continued expression of Oct4, Sox2, and Nanog. Foxd3 functions to repress differentiation and promote ESC survival independently of these core pluripotency factors. Conditional knockout (tamoxifen-inducible Cre) in ESCs, proliferation assays, apoptosis assays, clonal self-renewal assays, lineage marker analysis Stem cells (Dayton, Ohio) High 18653770
2010 FOXD3 levels are upregulated in mutant B-RAF melanoma cells following attenuation of B-RAF and MEK signaling (selectively in mutant B-RAF, not wild-type B-RAF cells). Ectopic FOXD3 expression causes G1 cell cycle arrest in melanoma cells via p53-dependent upregulation of p21(Cip1); p53 depletion prevents FOXD3-induced arrest. FOXD3 does not alter ERK1/2 activation by mutant B-RAF. siRNA knockdown, ectopic overexpression, MEK inhibitor treatment, cell cycle analysis, p53/p21 depletion rescue experiments Cancer research High 20332228
2011 Neural crest stem cell multipotency requires Foxd3 to maintain neural potential and repress mesenchymal fates. Conditional NC-specific Foxd3 deletion causes loss of neural NC derivatives and ectopic NC-derived vascular smooth muscle cells in the aorta, along with precocious osteoblast/chondrocyte differentiation. Individual mutant NC cells from different axial levels lose neural and gain myofibroblast potential, demonstrating that Foxd3 maintains a cell-intrinsic fate restriction. Conditional neural crest-specific knockout mouse, lineage tracing, clonal in vitro fate assays, histological and molecular analysis Development (Cambridge, England) High 21228004
2011 Upregulation of FOXD3 following B-RAF/MEK inhibitor (PLX4032/PLX4720) treatment confers resistance to cell death in mutant B-RAF melanoma cells. siRNA-mediated knockdown of FOXD3 significantly enhances cell death after PLX4032/4720 treatment. FOXD3 upregulation is attenuated in non-adherent conditions, and ectopic FOXD3 expression in non-adherent cells reduces PLX4720-induced cell death. siRNA knockdown, ectopic overexpression, pharmacological B-RAF/MEK inhibition, cell death assays, adherent vs. non-adherent culture conditions Oncogene Medium 21996740
2011 FOXD3 inhibits migration, invasion, and spheroid outgrowth of mutant B-RAF melanoma cells. FOXD3 directly binds the Rnd3 promoter and represses Rnd3 expression at both mRNA and protein levels. Inhibition of ROCK (a downstream effector of RhoA, which Rnd3 normally inhibits) partially restores migration in FOXD3-expressing cells, placing FOXD3 upstream of Rnd3-RhoA-ROCK signaling. Ectopic overexpression, chromatin immunoprecipitation (ChIP) at Rnd3 promoter, migration/invasion assays, ROCK inhibitor rescue Molecular cancer research : MCR Medium 21478267
2011 tfap2a and foxd3 are jointly necessary and sufficient for neural crest induction in zebrafish. Double mutant mob;mos embryos completely lack all neural crest-derived tissues. foxd3 is expressed in dorsal mesendoderm/ectoderm during gastrulation prior to neural crest induction. foxd3 overexpression enhances tfap2a-driven ectopic neural crest induction. Loss of both genes expands Bmp signaling and suppresses canonical Wnt targets, disrupting neural crest induction domain. Zebrafish double mutant analysis, overexpression, Bmp/Wnt pathway readouts in double mutants Developmental biology High 21963426
2012 Two FoxD3 neural crest enhancers (NC1 and NC2) drive spatially and temporally distinct expression in cranial vs. vagal/trunk neural crest subpopulations. Mutational analysis, in vivo ChIP, and morpholino knockdowns reveal that Pax7 and Msx1/2 cooperate with Ets1 to bind the cranial NC1 enhancer, while at vagal/trunk levels these factors function with Zic1, which directly binds NC2. This reveals differential upstream regulation of FoxD3 across neural crest subpopulations. Enhancer reporter assays, mutational analysis of enhancer elements, in vivo ChIP, morpholino knockdown epistasis in chick/Xenopus PLoS genetics High 23284303
2013 Neural crest and Schwann cell progenitor-derived melanocytes are spatially segregated (epaxial vs. hypaxial domains). Both populations originate from the Foxd3 lineage but diverge at different times from Foxd3-positive progenitors. Gain- and loss-of-function experiments in avians and mice show Foxd3 is both sufficient and necessary for regulating the balance between melanocyte and Schwann cell development, and also regulates the switch between neuronal and glial fates in sensory ganglia. Lineage tracing, conditional knockout (mouse), gain-of-function (avian electroporation), loss-of-function experiments Proceedings of the National Academy of Sciences of the United States of America High 23858437
2006 FoxD3 is required for Nodal expression in the Xenopus Spemann organizer and this is essential for dorsal mesoderm formation. FoxD3 functions as a transcriptional repressor (Engrailed-FoxD3 mimics native activity; VP16-FoxD3 blocks it) to induce mesodermal genes and convergent extension. FoxD3 induces mesoderm non-cell-autonomously, consistent with induction of secreted Nodal-related factors. Nodal signaling inhibitors block FoxD3-mediated mesoderm induction. Xenopus overexpression (native, Engrailed-fusion, VP16-fusion FoxD3), morpholino knockdown, explant assays, Nodal inhibitor rescue Development (Cambridge, England) High 17092955
2007 HDAC1 (colgate/hdac1) represses foxd3 expression in zebrafish neural crest to permit mitfa-dependent melanogenesis. In hdac1 mutants, foxd3 expression is elevated and mitfa-positive melanoblasts are severely reduced. Partial reduction of Foxd3 in hdac1 mutants rescues mitfa expression and melanophore defects. Foxd3 physically interacts with the mitfa promoter, demonstrating that Foxd3 directly represses mitfa transcription. Zebrafish hdac1 mutant analysis, morpholino knockdown of foxd3, chromatin association assay at mitfa promoter Developmental biology High 18068699
2010 In zebrafish neural crest, Foxd3 and Mitf regulate a bi-potent pigment precursor fate decision: Foxd3 suppresses mitfa to promote iridophore development, while Mitfa promotes melanophore fate. Loss of foxd3 causes fewer iridophores; loss of mitfa causes supernumerary iridophores. Double foxd3;mitfa mutants restore iridophore numbers. Foxd3 co-localizes with pnp4a (novel iridophore marker) and is necessary for its expression. Cell lineage analysis with EosFP shows both melanophores and iridophores derive from a mitfa+ precursor. Zebrafish single and double mutant analysis, in situ hybridization, photoconvertible lineage tracing (EosFP), genetic epistasis Developmental biology High 20460180
2009 Disc1 functions upstream of foxd3 and sox10 in zebrafish cranial neural crest (CNC): loss of Disc1 results in persistent CNC cell medial migration and enhanced expression of foxd3 and sox10. General CNC cell motility (speed) is unaffected. Disc1 is proposed to function in transcriptional repression of foxd3 and sox10, mediating CNC migration and differentiation. Zebrafish morpholino knockdown of disc1, live imaging of CNC migration, in situ hybridization for foxd3 and sox10 Development (Cambridge, England) Medium 19570850
2006 Foxd3 directly transactivates the myf5 promoter by interacting with the -82/-62 cassette element, as identified by yeast one-hybrid assay and confirmed by dual-luciferase reporter assay. Morpholino knockdown of foxd3 dramatically reduces myf5 expression in somites and adaxial cells (but not presomitic mesoderm), without affecting myod. Pax3 acts upstream of foxd3 to maintain myf5 expression; foxd3 mRNA rescues myf5 expression in pax3 morphants. Yeast one-hybrid assay, dual-luciferase reporter assay, zebrafish morpholino knockdown, mRNA rescue experiment Developmental biology Medium 16386728
2010 Foxd3 and Pax3 genetically interact in cardiac neural crest (NC) development. NC-specific homozygous Foxd3 deletion combined with Pax3 heterozygosity causes fully penetrant persistent truncus arteriosus, severe thymus hypoplasia, increased NC cell death in neural folds, and near-complete absence of NC caudal to pharyngeal arch 1 — phenotypes absent in single mutants. This gene dosage-sensitive interaction demonstrates Foxd3 and Pax3 act together to maintain cardiac NC progenitor survival. Conditional NC-specific Foxd3 knockout combined with Pax3 heterozygous knockout (compound mutant), histology, apoptosis assays Genesis (New York, N.Y. : 2000) High 21254333
2013 FOXD3 directly binds the NDRG1 promoter to activate its transcription in neuroblastoma cells, as shown by luciferase reporter and chromatin immunoprecipitation assays. FOXD3 overexpression suppresses growth, invasion, metastasis, and angiogenesis of neuroblastoma cells in vitro and in vivo; FOXD3 knockdown promotes these properties. Rescue experiments show that NDRG1 restoration prevents FOXD3-mediated changes, and that FOXD3 acts through NDRG1 to regulate VEGF and MMP9. Luciferase reporter assay, ChIP, siRNA knockdown, ectopic overexpression, xenograft tumor model, rescue experiments with NDRG1 restoration Oncotarget Medium 24269992
2014 FOXD3 directly binds the promoter of miR-137 and activates its transcription in hepatocellular carcinoma (HCC) cells. miR-137 targets AKT2, and FOXD3-regulated miR-137 inhibits HCC growth and metastasis via suppression of the AKT2/mTOR pathway. In vivo studies confirm the FoxD3/miR-137/AKT2 regulatory network. Luciferase reporter assay, ChIP at miR-137 promoter, overexpression/knockdown, AKT2 rescue experiments, xenograft model Oncotarget Medium 24970808
2016 FOXD3 acts as a dual-function regulator of enhancer activity in pluripotent cells: it recruits the SWI/SNF chromatin remodeling ATPase BRG1 to promote nucleosome removal (enhancer priming/opening) while simultaneously recruiting histone deacetylases HDAC1/2 to inhibit maximal enhancer activation. FOXD3 binds distinct enhancer sites in ESCs vs. epiblast stem cells (EpiSCs), modulating developmental potential as cells differentiate from naive to primed pluripotency. ChIP-seq, ATAC-seq/chromatin accessibility assays, co-immunoprecipitation for BRG1 and HDAC1/2, conditional Foxd3 deletion in ESCs and EpiSCs Cell stem cell High 26748757
2016 Foxd3 promotes exit from naive pluripotency by decommissioning active enhancers associated with naive pluripotency and early germline genes. As a repressor, Foxd3 dismantles a significant fraction of the naive pluripotency expression program during the ESC-to-EpiSC transition. Subsequently, Foxd3 must itself be silenced in primed pluripotent cells to allow re-activation of genes required for primordial germ cell (PGC) specification. Conditional Foxd3 knockout, ChIP-seq for enhancer marks (H3K27ac), RNA-seq, genome-wide chromatin analysis comparing ESC and EpiSC states Cell stem cell High 26748758
2015 PAX3 and FOXD3 cooperate to drive CXCR4 expression in melanoma cells through a conserved intronic enhancer element. Inhibition of PAX3 and FOXD3 reduces CXCR4 expression, slows cell growth and migration, and decreases chemotaxis; these effects are rescued by CXCR4 overexpression. Overexpression of PAX3 and FOXD3 drives increased CXCR4 levels. siRNA knockdown, overexpression, enhancer reporter assays, migration/invasion/chemotaxis assays, CXCR4 rescue experiments The Journal of biological chemistry Medium 26205821
2013 Foxd3 conditional deletion in mouse embryonic stem cells causes misregulation of genes involved in embryonic organ development, epithelium development, and epithelial differentiation. Six novel transcriptional targets of Foxd3 were identified: Sox4, Safb, Sox15, Fosb, Pmaip1, and Smarcd3. Data suggest Foxd3 functions upstream of genes required for skeletal muscle development. Conditional Foxd3 deletion, microarray gene expression analysis, identification of downstream targets Stem cell research Medium 24270162
2016 CHD7, Oct3/4, Sox2, and Nanog directly occupy multiple conserved regions (mE1, mE2, mE3) of the mouse FoxD3 locus in a BMP2/Wnt3a-dependent manner to induce FoxD3 expression during neural crest-derived stem cell (NCSC) formation. FoxD3 in turn promotes Sox10 expression required for NCSC formation. Histone H3K4 mono- or trimethylation is also required at the FoxD3 locus. ChIP assay at FoxD3 regulatory regions, siRNA knockdown of CHD7/Oct3/4/Sox2/Nanog, histone methyltransferase inhibition The FEBS journal Medium 27579714
2016 FOXD3 is validated as a transcription factor that directly binds the miR-214 promoter (by ChIP assay) in colorectal cancer (CRC) cells, activating miR-214 expression. miR-214 targets MED19. The FOXD3/miR-214/MED19 axis mediates inhibition of proliferation, invasion, and metastasis in CRC in vitro and in vivo. ChIP assay at miR-214 promoter, dual-luciferase reporter for MED19 targeting, overexpression/knockdown, xenograft model British journal of cancer Medium 27811858
2017 FOXD3 knockdown in colon cancer cells activates the EGFR/Ras/Raf/MEK/ERK pathway, increases proliferation, invasion, and inhibits apoptosis; these effects are reversed by EGFR blocking. FOXD3 functions as a transcriptional repressor that suppresses EGFR-Ras-Raf-MEK-ERK signaling in colon cancer. siRNA knockdown, ectopic overexpression, pharmacological EGFR inhibition, xenograft model, Western blotting for pathway components Oncotarget Medium 27926503
2020 FOXD3 regulates VISTA (V-domain Ig suppressor of T cell activation) expression in melanoma cells at the transcript level. BRAF inhibition upregulates FOXD3 and concurrently reduces VISTA expression. Tumor cell-specific VISTA expression promotes tumor onset in vivo, associated with increased intratumoral T regulatory cells and enhanced PDL-1 on tumor-infiltrating macrophages. siRNA knockdown, BRAF inhibitor treatment, in vivo tumor growth assay, flow cytometry for immune infiltrate Cell reports Medium 31940493

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 To err (meiotically) is human: the genesis of human aneuploidy. Nature reviews. Genetics 1832 11283700
2009 Apoptosis and cancer: the genesis of a research field. Nature reviews. Cancer 580 19550425
2009 The mammalian ovary from genesis to revelation. Endocrine reviews 567 19776209
2002 Specialized DNA polymerases, cellular survival, and the genesis of mutations. Science (New York, N.Y.) 359 12040171
2005 The genesis and evolution of homeobox gene clusters. Nature reviews. Genetics 350 16341069
2005 Inflammation in the genesis and perpetuation of atrial fibrillation. European heart journal 349 15975993
2010 The genesis and evolution of high-grade serous ovarian cancer. Nature reviews. Cancer 332 20944665
2004 Timing and topography of cell genesis in the rat retina. The Journal of comparative neurology 311 15164429
2007 MicroRNA expression is required for pancreatic islet cell genesis in the mouse. Diabetes 294 17804764
2004 Cell signaling and the genesis of neuropathic pain. Science's STKE : signal transduction knowledge environment 279 15454629
2002 Requirement for Foxd3 in maintaining pluripotent cells of the early mouse embryo. Genes & development 263 12381664
2001 Requirement of FoxD3-class signaling for neural crest determination in Xenopus. Development (Cambridge, England) 217 11493569
2005 Genesis of alcohol-induced craniofacial dysmorphism. Experimental biology and medicine (Maywood, N.J.) 182 15956766
2015 Inflammation and its genesis in cystic fibrosis. Pediatric pulmonology 153 26335954
2006 Zebrafish foxd3 is selectively required for neural crest specification, migration and survival. Developmental biology 151 16499899
2011 Perivascular instruction of cell genesis and fate in the adult brain. Nature neuroscience 127 22030549
2010 Interplay between Foxd3 and Mitf regulates cell fate plasticity in the zebrafish neural crest. Developmental biology 127 20460180
2014 The genesis of tyrosine phosphorylation. Cold Spring Harbor perspectives in biology 124 24789824
2009 Genesis, effects and fates of repeats in prokaryotic genomes. FEMS microbiology reviews 123 19396957
2012 Dynamic and differential regulation of stem cell factor FoxD3 in the neural crest is Encrypted in the genome. PLoS genetics 118 23284303
2017 Emerging role for dysregulated decidualization in the genesis of preeclampsia. Placenta 117 28693893
2012 Genesis of the myofibroblast in lung injury and fibrosis. Proceedings of the American Thoracic Society 108 22802289
2009 Role of cannabis and endocannabinoids in the genesis of schizophrenia. Psychopharmacology 108 19629449
1992 Epinephrine and the genesis of hypertension. Hypertension (Dallas, Tex. : 1979) 104 1309718
1980 Meiosis and ascospore genesis in Neurospora. European journal of cell biology 103 6450683
2014 FoxD3-regulated microRNA-137 suppresses tumour growth and metastasis in human hepatocellular carcinoma by targeting AKT2. Oncotarget 99 24970808
2013 Neural crest and Schwann cell progenitor-derived melanocytes are two spatially segregated populations similarly regulated by Foxd3. Proceedings of the National Academy of Sciences of the United States of America 96 23858437
2009 The genesis of cerebellar interneurons and the prevention of neural DNA damage require XRCC1. Nature neuroscience 94 19633665
1998 The winged helix transcription factor Hfh2 is expressed in neural crest and spinal cord during mouse development. Mechanisms of development 94 9767163
2011 Neural crest stem cell multipotency requires Foxd3 to maintain neural potential and repress mesenchymal fates. Development (Cambridge, England) 93 21228004
1998 Molecular changes during the genesis of human gliomas. Seminars in surgical oncology 91 9407626
2011 Tfap2a and Foxd3 regulate early steps in the development of the neural crest progenitor population. Developmental biology 88 21963426
2006 Sex hormones and the genesis of autoimmunity. Archives of dermatology 87 16549717
2021 Deficient H2A.Z deposition is associated with genesis of uterine leiomyoma. Nature 86 34349258
2019 The genesis and evolution of bead-based multiplexing. Methods (San Diego, Calif.) 86 30659874
2008 Regulation of embryonic stem cell self-renewal and pluripotency by Foxd3. Stem cells (Dayton, Ohio) 86 18653770
2020 Singlet Oxygen Metabolism: From Genesis to Signaling. Frontiers in plant science 83 31969891
2021 The Retromer Complex: From Genesis to Revelations. Trends in biochemical sciences 82 33526371
2016 FOXD3 Regulates Pluripotent Stem Cell Potential by Simultaneously Initiating and Repressing Enhancer Activity. Cell stem cell 80 26748757
2014 Genesis and morphogenesis of limb synovial joints and articular cartilage. Matrix biology : journal of the International Society for Matrix Biology 79 25172830
1990 The genesis of alcoholic brain tissue injury. Alcohol and alcoholism (Oxford, Oxfordshire) 79 2198037
2019 Genesis of the αβ T-cell receptor. PLoS computational biology 74 30830899
2010 FOXD3 is a mutant B-RAF-regulated inhibitor of G(1)-S progression in melanoma cells. Cancer research 74 20332228
2010 Mitochondrial protein import and the genesis of steroidogenic mitochondria. Molecular and cellular endocrinology 73 21147195
2003 Genesis and pathogenesis of lymphatic vessels. Cell and tissue research 73 12942362
2009 Disc1 regulates foxd3 and sox10 expression, affecting neural crest migration and differentiation. Development (Cambridge, England) 71 19570850
2020 FOXD3 Regulates VISTA Expression in Melanoma. Cell reports 70 31940493
2016 Foxd3 Promotes Exit from Naive Pluripotency through Enhancer Decommissioning and Inhibits Germline Specification. Cell stem cell 68 26748758
2015 Plant cutin genesis: unanswered questions. Trends in plant science 67 26115781
2007 colgate/hdac1 Repression of foxd3 expression is required to permit mitfa-dependent melanogenesis. Developmental biology 64 18068699
2013 FOXD3 is a novel tumor suppressor that affects growth, invasion, metastasis and angiogenesis of neuroblastoma. Oncotarget 63 24269992
2004 Slow axonal transport and the genesis of neuronal morphology. Journal of neurobiology 62 14598366
2021 Gut Microbiota Influence in Hematological Malignancies: From Genesis to Cure. International journal of molecular sciences 61 33498529
2017 Long noncoding RNA FOXD3-AS1 regulates oxidative stress-induced apoptosis via sponging microRNA-150. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 60 28655711
2017 Retracted: Risk-Associated Long Noncoding RNA FOXD3-AS1 Inhibits Neuroblastoma Progression by Repressing PARP1-Mediated Activation of CTCF. Molecular therapy : the journal of the American Society of Gene Therapy 58 29398485
2019 LncRNA FOXD3-AS1 promotes proliferation, invasion and migration of cutaneous malignant melanoma via regulating miR-325/MAP3K2. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 57 31541886
2014 Physiological protein aggregation run amuck: stress granules and the genesis of neurodegenerative disease. Discovery medicine 57 24411700
2023 The genesis of human hematopoietic stem cells. Blood 56 37339578
2015 Macrophage and Innate Lymphoid Cell Interplay in the Genesis of Fibrosis. Frontiers in immunology 55 26635811
2011 Adaptive upregulation of FOXD3 and resistance to PLX4032/4720-induced cell death in mutant B-RAF melanoma cells. Oncogene 55 21996740
2021 Exosomal lncRNA FOXD3-AS1 upregulates ELAVL1 expression and activates PI3K/Akt pathway to enhance lung cancer cell proliferation, invasion, and 5-fluorouracil resistance. Acta biochimica et biophysica Sinica 53 34605863
2016 Role of STAT3 in Genesis and Progression of Human Malignant Gliomas. Molecular neurobiology 51 27660268
2017 FOXD3 is a tumor suppressor of colon cancer by inhibiting EGFR-Ras-Raf-MEK-ERK signal pathway. Oncotarget 49 27926503
2015 A Place at the Table: LTD as a Mediator of Memory Genesis. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 47 25993993
2014 Using zebrafish to study podocyte genesis during kidney development and regeneration. Genesis (New York, N.Y. : 2000) 47 24920186
1993 The role of gene mutations in the genesis of familial cancers. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 46 8102106
2002 Schizophrenia: genesis, receptorology and current therapeutics. Current medicinal chemistry 45 11945123
2006 FoxD3 regulation of Nodal in the Spemann organizer is essential for Xenopus dorsal mesoderm development. Development (Cambridge, England) 44 17092955
2021 Role of inflammatory cytokines in genesis and treatment of atherosclerosis. Trends in cardiovascular medicine 40 33571665
2016 The FOXD3/miR-214/MED19 axis suppresses tumour growth and metastasis in human colorectal cancer. British journal of cancer 40 27811858
2011 FOXD3 regulates migration properties and Rnd3 expression in melanoma cells. Molecular cancer research : MCR 39 21478267
2010 Genesis of teratogen-induced holoprosencephaly in mice. American journal of medical genetics. Part C, Seminars in medical genetics 39 20104601
2006 Foxd3 mediates zebrafish myf5 expression during early somitogenesis. Developmental biology 39 16386728
2019 Genes CEP55, FOXD3, FOXF2, GNAO1, GRIA4, and KCNA5 as potential diagnostic biomarkers in colorectal cancer. BMC medical genomics 38 30987631
1996 Spatiotemporal gradients of cell genesis in the primate retina. Perspectives on developmental neurobiology 38 8931090
1986 Platelet and vessel wall interaction and the genesis of atherosclerosis. Clinics in haematology 36 2942331
2020 LncRNA FOXD3-AS1 knockdown protects against cerebral ischemia/reperfusion injury via miR-765/BCL2L13 axis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 35 33068927
2017 Changing mutational and adaptive landscapes and the genesis of cancer. Biochimica et biophysica acta. Reviews on cancer 34 28167050
2009 Retrotransposons, reverse transcriptase and the genesis of new genetic information. Gene 34 19631262
2001 Genesis of pituitary adenomas: state of the art. Journal of neuro-oncology 33 11761437
2023 Genesis of clinical and subclinical endometritis in dairy cows. Reproduction (Cambridge, England) 32 37294111
1975 Genesis and genetics of retinoblastoma. Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde 32 1097980
2021 Genetic control of retinal ganglion cell genesis. Cellular and molecular life sciences : CMLS 31 33782712
2020 LncRNA FOXD3-AS1 promoted chemo-resistance of NSCLC cells via directly acting on miR-127-3p/MDM2 axis. Cancer cell international 31 32742197
2022 The Subventricular Zone in Glioblastoma: Genesis, Maintenance, and Modeling. Frontiers in oncology 30 35359410
2019 Long non-coding RNA FOXD3-AS1 aggravates ischemia/reperfusion injury of cardiomyocytes through promoting autophagy. American journal of translational research 30 31632535
2016 The genesis and presentation of anxiety in disorders of autonomic overexcitation. Autonomic neuroscience : basic & clinical 30 27865628
2020 Immune-mediated genesis of multiple sclerosis. Journal of translational autoimmunity 29 32743522
2014 Oncogenic microRNAs in the genesis of leukemia and lymphoma. Current pharmaceutical design 28 24479800
2019 lncRNA FOXD3-AS1 is associated with clinical progression and regulates cell migration and invasion in breast cancer. Cell biochemistry and function 26 31017311
2011 Novel concepts in the genesis of hypertension: role of LOX-1. Cardiovascular drugs and therapy 26 21912849
2021 Fractalkine signaling regulates oligodendroglial cell genesis from SVZ precursor cells. Stem cell reports 25 34270934
2016 CHD7, Oct3/4, Sox2, and Nanog control FoxD3 expression during mouse neural crest-derived stem cell formation. The FEBS journal 25 27579714
2012 The role of stem cells and progenitors in the genesis of medulloblastoma. Experimental neurology 25 23178582
2015 FOXD3 suppresses tumor growth and angiogenesis in non-small cell lung cancer. Biochemical and biophysical research communications 24 26341266
2021 MiR-328-3p inhibits lung adenocarcinoma-genesis by downregulation PYCR1. Biochemical and biophysical research communications 23 33706104
2015 PAX3 and FOXD3 Promote CXCR4 Expression in Melanoma. The Journal of biological chemistry 22 26205821
2013 Transcriptional targets of Foxd3 in murine ES cells. Stem cell research 22 24270162
2010 Functional interaction between Foxd3 and Pax3 in cardiac neural crest development. Genesis (New York, N.Y. : 2000) 22 21254333
2009 Promoter methylation in the genesis of gastrointestinal cancer. Yonsei medical journal 22 19568590

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