Affinage

GBX2

Homeobox protein GBX-2 · UniProt P52951

Length
348 aa
Mass
37.3 kDa
Annotated
2026-04-28
75 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GBX2 is a homeodomain transcription factor that functions primarily as a transcriptional repressor to establish regional boundaries in the developing nervous system and other tissues. GBX2 represses Otx2 through direct binding to the Otx2 FM enhancer (competing with POU-III factors for the TAATTA motif) and through recruitment of Groucho/Tle corepressors via an engrailed homology 1 (eh1) motif, thereby positioning the Fgf8-expressing isthmic organizer at the Otx2/Gbx2 interface and specifying anterior hindbrain identity (PMID:9247335, PMID:22566684, PMID:17060451). Acting downstream of FGF8 and Wnt/β-catenin signaling, GBX2 controls diverse developmental programs including neural crest specification (cooperating with Zic1), thalamocortical axon guidance (regulating a Robo1/Robo2-LIM transcription factor code), striatal cholinergic interneuron generation, inner ear morphogenesis, and retinal amacrine cell dendritic stratification via Slit-Robo signaling (PMID:19736322, PMID:23136391, PMID:21048141, PMID:15829521, PMID:33207201). In embryonic stem cells, GBX2 is a direct LIF/Stat3 target that maintains naïve pluripotency through induction of Klf4, and its overexpression is sufficient to reprogram epiblast stem cells to ground-state ESCs (PMID:23345404, PMID:28848051).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1997 High

    Establishing that GBX2 is required for anterior hindbrain (r1–r3) specification and isthmic organizer maintenance resolved the question of which transcription factor confers hindbrain identity at the MHB.

    Evidence Gbx2 null mouse with loss of cerebellum, isthmic nuclei, and motor nerve V; marker analysis by in situ hybridization

    PMID:9247335

    Open questions at the time
    • Mechanism of Gbx2-mediated repression unknown
    • Direct transcriptional targets unidentified
    • Relationship to Otx2 not yet tested genetically
  2. 1997 High

    Identification of GBX2 as a direct target of the v-Myb oncoprotein revealed an unexpected role outside the nervous system, in hematopoietic differentiation.

    Evidence Retroviral transduction and reporter assays in chicken myeloblasts; ectopic GBX2 induces monocytic differentiation

    PMID:9346236

    Open questions at the time
    • Physiological relevance of GBX2 in normal hematopoiesis not established
    • Downstream targets of GBX2 in myeloblasts not identified
  3. 1999 High

    Placing GBX2 downstream of FGF8 signaling established the epistatic hierarchy at the MHB: FGF8 induces Gbx2, which in turn represses Otx2.

    Evidence FGF8b-soaked bead implantation in mouse brain explants and Wnt1-Fgf8b transgenic embryos

    PMID:10518499

    Open questions at the time
    • Whether FGF8 regulation of Gbx2 is direct or indirect was unresolved
    • Feedback from Gbx2 to Fgf8 not yet dissected
  4. 2000 High

    Demonstrating mutual repression between Otx2 and Gbx2 by gain-of-function in chick established that their interface positions the Fgf8 domain, answering how the MHB is spatially defined.

    Evidence In ovo electroporation of Otx2 and Gbx2 in chick mesencephalon/metencephalon with marker analysis

    PMID:10704829

    Open questions at the time
    • Molecular mechanism of mutual repression (direct vs. indirect) unknown
    • Whether the same logic operates in mammals not yet tested genetically
  5. 2001 High

    Compound Otx2/Gbx2 mutant analysis proved that Fgf8 activation is independent of both factors, while Gbx2 is required for FGF8-mediated Otx2 repression, refining the epistatic model.

    Evidence Otx1/Otx2/Gbx2 compound mutant mice with Fgf8 activation throughout anterior neural plate

    PMID:11124114 PMID:11731459

    Open questions at the time
    • Direct DNA-binding targets of Gbx2 at the MHB not identified
    • Mechanism by which Gbx2 represses transcription not known
  6. 2001 High

    Activator/repressor domain-swap experiments in Xenopus established that Gbx2 functions as a transcriptional repressor, not an activator, resolving its mode of action.

    Evidence Obligatory VP16-activator and EnR-repressor fusions of Xgbx2a injected into Xenopus embryos

    PMID:11850185

    Open questions at the time
    • Corepressor identity unknown
    • Whether repressor function is conserved in mammals not directly tested
  7. 2002 High

    Conditional deletion after E9 showed Gbx2 is required for Fgf8 maintenance but not for Otx2 repression in r1 at later stages, revealing stage-dependent redundancy.

    Evidence Conditional Gbx2 knockout in r1 with temporal control, marker gene analysis

    PMID:12367504

    Open questions at the time
    • Identity of the Gbx2-independent Otx2 repressor in r1 unknown
    • Mechanism of Gbx2 dose-dependence not resolved
  8. 2005 High

    Discovery that Gbx2 is required for inner ear morphogenesis (endolymphatic duct, semicircular canals) extended its role beyond the brain and showed it restricts Otx2 and promotes Wnt2b/Dlx5 in the otic vesicle.

    Evidence Gbx2 null mouse inner ear analysis with in situ hybridization for downstream targets

    PMID:15829521

    Open questions at the time
    • Whether Gbx2 directly binds otic target gene regulatory elements not shown
    • Relationship to Fgf signaling in the ear not defined
  9. 2005 High

    Gbx2 null mice display interrupted aortic arch type B and neural crest cell patterning defects, revealing a role in cardiovascular development through genetic interaction with Fgf8.

    Evidence Gbx2 null and Fgf8/Gbx2 compound mutant mouse analysis, neural crest fate and vascular morphology

    PMID:15996652

    Open questions at the time
    • Direct transcriptional targets of Gbx2 in pharyngeal arch tissue unknown
    • Whether defects are cell-autonomous in NCC not resolved
  10. 2006 High

    Identification of the eh1 motif in Gbx2 and its physical interaction with Groucho/Tle corepressors provided the first biochemical mechanism for Gbx2-mediated transcriptional repression of Otx2.

    Evidence Co-immunoprecipitation of Gbx2 and Groucho/Tle, heat-shock-driven wild-type and eh1-mutant Gbx2 in medaka embryos

    PMID:17060451

    Open questions at the time
    • Whether NuRD or other corepressor complexes also participate in Gbx2 repression not tested
    • Structural details of Gbx2-Groucho interaction unknown
  11. 2006 High

    A Gbx2 hypomorphic allele demonstrated that a threshold level of Gbx2 distinguishes r1 from isthmus identity, establishing dose-dependent control of regional specification.

    Evidence Gbx2neo hypomorphic allele (6–10% expression) with quantitative molecular and proliferation analysis

    PMID:16651541

    Open questions at the time
    • Molecular basis for differential dose requirements in r1 vs. r2/r3 unknown
  12. 2009 High

    ChIP and transgenesis demonstrated that Gbx2 is a direct Wnt/β-catenin target and the earliest factor in the neural crest specification cascade, acting with Zic1 upstream of Pax3 and Msx1.

    Evidence ChIP on Gbx2 regulatory elements, morpholino knockdown, overexpression, and epistasis in Xenopus

    PMID:19736322

    Open questions at the time
    • Whether Wnt directly activates Gbx2 in mammalian neural crest not confirmed
    • Mechanism of Gbx2-Zic1 cooperation not biochemically defined
  13. 2009 High

    Genetic fate mapping revealed that Gbx2-expressing cells form lineage-restriction boundaries delineating the thalamus, and Gbx2 acts cell-non-autonomously to prevent thalamic neurons from populating epithalamus and pretectum.

    Evidence Gbx2-Cre fate mapping, chimeric mouse analysis, conditional knockout

    PMID:19279136

    Open questions at the time
    • Signals mediating the cell-non-autonomous effect unidentified
    • Downstream transcriptional targets in thalamic progenitors not defined
  14. 2010 High

    Gbx2 lineage tracing in the medial ganglionic eminence showed it marks the precursors of nearly all striatal cholinergic interneurons, and conditional deletion disrupts their distribution and neurite outgrowth.

    Evidence Gbx2-CreERT2 inducible fate mapping, MGE-specific conditional KO, immunofluorescence

    PMID:21048141

    Open questions at the time
    • Direct transcriptional targets of Gbx2 in cholinergic interneuron specification unknown
    • Whether Gbx2 acts on migration, differentiation, or survival not fully separated
  15. 2011 High

    Demonstration that Gbx2+ and Otx2+ cell populations sort from each other as early as E7.5 and that Gbx2 null cells cross into midbrain territory established that Gbx2 controls cell identity that drives MHB lineage restriction.

    Evidence Gbx2CreER knock-in fate mapping at multiple embryonic stages, Gbx2 null and partial Fgf8 deletion

    PMID:21266408

    Open questions at the time
    • Cell adhesion molecules mediating sorting at the MHB not identified
  16. 2012 High

    ChIP and EMSA showed that Gbx2 directly binds a TAATTA motif in the Otx2 FM enhancer, competing with POU-III factors for the same site, providing the first direct DNA-binding mechanism for Otx2 repression.

    Evidence ChIP, EMSA, miRNA knockdown, and reporter assays in P19 cells

    PMID:22566684

    Open questions at the time
    • Whether this competitive mechanism operates genome-wide not tested
    • Crystal structure of Gbx2-DNA complex unavailable
  17. 2012 High

    Gbx2 was shown to intrinsically control thalamocortical axon guidance by regulating a LIM-domain/Robo transcriptional code: repressing Lmo3 and Lhx9 to enable proper Robo1/Robo2 expression.

    Evidence Conditional Gbx2 deletion at different stages, explant culture, mosaic analysis, promoter binding assays

    PMID:23136391

    Open questions at the time
    • Whether Gbx2 directly binds Lmo3 and Lhx9 promoters not confirmed by ChIP
    • Contribution of other axon guidance receptors not assessed
  18. 2012 High

    ChIP-Seq in prostate cancer cells identified genome-wide GBX2 binding targets including ROBO1, SLIT3, NOTCH2, and EEF1A1, expanding the known direct target repertoire beyond developmental contexts.

    Evidence ChIP-Seq, gel shift validation, reporter assays, Gbx2 null mouse neural crest analysis

    PMID:23144817

    Open questions at the time
    • Functional significance of most ChIP-Seq targets not validated in vivo
    • Whether GBX2 activates or represses each target not systematically determined
  19. 2013 Medium

    Establishing Gbx2 as a LIF/Stat3 target that maintains naïve pluripotency in mESCs and can reprogram epiblast stem cells revealed a stem cell function independent of its neural patterning roles.

    Evidence Gbx2 overexpression sustains mESC self-renewal without LIF; epiblast-to-ESC reprogramming assay

    PMID:23345404

    Open questions at the time
    • Direct binding of Stat3 to the Gbx2 locus not demonstrated
    • Downstream mediators of Gbx2 in ESC self-renewal were initially unresolved
  20. 2017 Medium

    Identification of Klf4 as a mediator of Gbx2's self-renewal function in ESCs resolved how a developmental transcription factor maintains naïve pluripotency.

    Evidence RNA-Seq target identification, Klf4 knockdown epistasis in ESC self-renewal and reprogramming assays

    PMID:28848051

    Open questions at the time
    • Whether Gbx2 directly binds the Klf4 promoter not confirmed by ChIP
    • Other Gbx2 targets contributing to pluripotency not identified
  21. 2020 High

    Genetic labeling and electrophysiology identified Gbx2 as a marker and specification factor for two distinct retinal amacrine cell subtypes, extending its role to retinal circuit assembly.

    Evidence Gbx2CreERT2-IRES-EGFP labeling, RNA-seq, patch-clamp recording, morphological analysis in mouse retina

    PMID:33207201

    Open questions at the time
    • Downstream transcriptional targets controlling amacrine cell identity not fully defined
    • Mechanism by which Gbx2 controls dendritic stratification not yet identified
  22. 2023 Medium

    Robo1/Robo2 were identified as direct effectors of Gbx2 in retinal amacrine cells, phenocopying Gbx2 mutant dendritic misprojections and establishing Slit-Robo signaling as the dendritic stratification mechanism downstream of Gbx2.

    Evidence (preprint) Robo1/2 conditional KO phenocopy of Gbx2 mutant, Slit1/2 localization analysis in mouse retina

    PMID:37577554

    Open questions at the time
    • Not yet peer-reviewed
    • Whether Gbx2 directly binds Robo1/2 regulatory elements in amacrine cells not shown
    • Other Gbx2-regulated guidance cues in retinal circuits not investigated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of Gbx2 DNA-binding selectivity and its context-dependent switch between repressor and activator modes across tissues remain unresolved.
  • No crystal or cryo-EM structure of GBX2 homeodomain-DNA complex
  • Mechanism determining whether Gbx2 activates (e.g., EEF1A1, Klf4) versus represses (e.g., Otx2, Lmo3) specific targets is unknown
  • Whether Gbx2 functions in adult tissue homeostasis beyond development is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-1266738 Developmental Biology 8 R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 4
Partners
KLF4LHX2OTX2ROBO1ROBO2TLEZIC1

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Gbx2 loss-of-function in mouse demonstrates it is required for specification and proliferation/survival of anterior hindbrain precursors (rhombomeres 1-3) and for maintaining normal Fgf8 and Wnt1 expression at the mid/hindbrain boundary (isthmic organizer); in the absence of Gbx2, isthmic nuclei, cerebellum, and motor nerve V fail to form. Loss-of-function mouse genetics (Gbx2 null allele), in situ hybridization for marker gene expression Development (Cambridge, England) High 9247335
1999 FGF8b can induce Gbx2 expression in mouse caudal forebrain explants and can repress Otx2 in midbrain explants; ectopic Fgf8b expression transforms midbrain and caudal forebrain into anterior hindbrain fate through expansion of the Gbx2 domain and repression of Otx2, placing FGF8 upstream of Gbx2 in the mid/hindbrain patterning pathway. FGF8b-soaked bead implantation in mouse embryonic explants, Wnt1-Fgf8b transgenic mouse line, in situ hybridization Development (Cambridge, England) High 10518499
2000 Otx2 and Gbx2 mutually repress each other's expression in the chick embryo brain; ectopic Otx2 expression in the metencephalon transforms it to optic tectum fate, while ectopic Gbx2 in mesencephalon shifts the caudal tectum boundary rostrally; the Otx2/Gbx2 interaction determines the site of Fgf8 expression and posterior tectum limit. In ovo electroporation gain-of-function in chick embryos, in situ hybridization for Fgf8 and other markers Mechanisms of development High 10704829
2001 Epistatic analysis in mouse brain explants shows GBX2 acts upstream of, or parallel to, FGF8 in repressing Otx2, and acts downstream of FGF8 in repression of Wnt1; EN transcription factors are required for FGF8-induced Pax5 expression; Gbx2 is among the first genes induced by FGF8 in diencephalic and midbrain explants. FGF8-bead explant culture, En1/2 double mutant analysis, Gbx2 mutant analysis, genetic epistasis Development (Cambridge, England) High 11124114
2001 OTX2 and GBX2 together are required for proper segregation of early regional identities anterior and posterior to the mid-hindbrain boundary; embryos deficient for both OTX2 and GBX2 show broad co-expression of forebrain, midbrain, and rostral hindbrain markers, and FGF8 is activated throughout the entire anterior neural plate, demonstrating FGF8 activation is independent of both OTX2 and GBX2; FGF8 cannot repress Otx2 without GBX2. Double mutant mouse genetics (Otx1/Otx2/Gbx2 compound mutants), in situ hybridization Development (Cambridge, England) High 11731459
2001 The Xenopus Gbx2 homologue (Xgbx2a) functions as a transcriptional repressor during early embryogenesis; it negatively regulates Otx2 and weakly activates Xcad2; its ability to induce head malformations is restricted to gastrula stages correlating with Otx2 repression; the earliest step of MHB formation involves mutual inhibitory interactions between Otx2 and Gbx2. Obligatory activator and repressor versions of Xgbx2a, hormone-inducible constructs, mRNA injection in Xenopus embryos Mechanisms of development High 11850185
2002 Gbx2 expressed in rhombomere 1 after E9 is required for maintenance of mid/hindbrain organizer gene expression (Fgf8); however, a Gbx2-independent pathway can repress Otx2 in r1 after E9, and mice lacking Gbx2 in r1 after E9 develop a cerebellum; Fgf8 expression domain expansion in Gbx2-CKO correlates with suppression of medial cerebellar growth. Conditional knockout mouse (Gbx2-CKO), in situ hybridization, histological analysis Neuron High 12367504
1997 GBX2 is a direct target of the v-Myb oncoprotein (AMV) in hematopoietic cells; GBX2 activation by c-Myb requires cell-surface signal transduction while AMV v-Myb constitutively induces GBX2; ectopic GBX2 expression in myeloblasts induces monocytic differentiation and cytokine independence; mutations in the Myb DNA-binding domain abrogate GBX2 induction and Myb/C-EBP collaboration. Retroviral transduction, transfection, reporter assays, morphological differentiation assays in chicken myeloblasts Cell High 9346236
2005 Gbx2 is required for inner ear morphogenesis in mice; Gbx2-/- inner ears lack the endolymphatic duct and show swelling of the membranous labyrinth, absence of anterior and posterior semicircular canals, and malformed saccule/cochlear duct; Gbx2 promotes dorsal fates by positively regulating Wnt2b and Dlx5, and promotes ventral fates by restricting Otx2 expression in the inner ear. Gbx2 null mouse analysis, gene expression analysis by in situ hybridization Development (Cambridge, England) High 15829521
2005 Loss of Gbx2 in mice results in aberrant neural crest cell patterning and fourth pharyngeal arch artery defects including interrupted aortic arch type B; Fgf8 and Gbx2 expression overlap in pharyngeal arches and they interact genetically during pharyngeal arch and cardiovascular development. Gbx2 null mouse genetics, neural crest cell fate analysis, vascular morphology analysis, compound Fgf8/Gbx2 mutant analysis Developmental biology High 15996652
2006 Gbx2 and Otx2 each contain engrailed homology 1 (eh1)-like motifs that physically interact with the WD40 domain of Groucho/Tle corepressor proteins; Groucho is required for the repression of Otx2 by Gbx2 (but not for repression of Gbx2 by Otx2); Groucho/Otx2 association is also required for Fgf8 repression at the MHB. Cell culture colocalization assay, co-immunoprecipitation, heat shock-induced expression of wild-type and mutant Otx2/Gbx2 in medaka embryos Molecular and cellular biology High 17060451
2007 Sall1 directly represses Gbx2 in a NuRD-dependent fashion; the Sall1 repression motif recruits the nucleosome remodeling and deacetylase (NuRD) complex; protein kinase C phosphorylates serine 2 of the Sall1 repression motif, and a phosphomimetic mutation of serine 2 disrupts NuRD binding and abolishes repression of Gbx2 in cell culture and Xenopus embryos. Xenopus embryo injection with mutant Sall1 constructs, cell culture reporter assays, domain mapping The Journal of biological chemistry High 17895244
2009 Gbx2 is the earliest factor in the neural crest (NC) genetic cascade, being directly activated by Wnt/beta-catenin signaling; ChIP and transgenesis demonstrate that Gbx2 regulatory elements respond directly to Wnt/beta-catenin; Gbx2 NC specifier activity depends on interaction with Zic1 and inhibition of preplacodal genes such as Six1; Gbx2 is upstream of Pax3 and Msx1. ChIP, transgenesis, antisense morpholino knockdown, overexpression in Xenopus, genetic epistasis Development (Cambridge, England) High 19736322
2009 Tbx1 controls cardiac neural crest cell migration during pharyngeal arch artery development by regulating Gbx2 expression in the pharyngeal surface ectoderm; Gbx2 downstream of Tbx1 provides directional cues to adjacent cardiac neural crest cells; the Slit/Robo signaling pathway is activated during cNCC migration and is affected in Gbx2 and Tbx1 mutants. Conditional mouse genetics, Gbx2 and Tbx1 mutant analysis, neural crest cell tracking, gene expression analysis Development (Cambridge, England) High 19700621
2009 Gbx2-expressing cells contribute to the entire thalamic nuclear complex; Gbx2-expressing cells and descendants form sharp lineage-restriction boundaries delineating the thalamus from pretectum, epithalamus, and prethalamus; without Gbx2, thalamus-derived cells abnormally populate epithalamus and pretectum; chimeric and mosaic analysis shows Gbx2 plays a cell-nonautonomous role in controlling segregation of postmitotic thalamic neurons. Genetic fate mapping (Gbx2-Cre), chimeric mouse analysis, in situ hybridization, cell lineage analysis Development (Cambridge, England) High 19279136
2010 Gbx2 lineage-derived cells in the medial ganglionic eminence (MGE) undergoing tangential migration exclusively give rise to almost all cholinergic interneurons in the striatum; deletion of Gbx2 throughout the embryo or specifically in the MGE results in abnormal distribution and significant reduction of cholinergic neurons in the striatum; early-born cholinergic precursors show abnormal neurite outgrowth in the absence of Gbx2. Inducible genetic fate mapping (Gbx2-CreERT2), conditional KO in MGE, histological and immunofluorescence analysis The Journal of neuroscience : the official journal of the Society for Neuroscience High 21048141
2011 Descendants of Gbx2+ cells as early as E7.5 do not cross the midbrain-hindbrain boundary (MHB); without Gbx2, hindbrain-born cells abnormally populate the entire midbrain, demonstrating Gbx2 specifies hindbrain fate; Gbx2+ and Otx2+ cells segregate from each other, indicating mutually exclusive expression drives cell sorting at the MHB; Fgf8, expressed just posterior to the lineage boundary, maintains the lineage-restricted boundary after E7.5 by a cell-autonomous effect on cell sorting in midbrain progenitors. Genetic inducible fate mapping (Gbx2CreER knock-in), partial Fgf8 deletion, FGF pathway activation assay, cell lineage analysis Development (Cambridge, England) High 21266408
2012 GBX2 controls thalamocortical axon (TCA) guidance intrinsically; loss of Gbx2 misroutes thalamic axons to ventral midbrain and dorsal midline of diencephalon; Gbx2 regulates Robo1 and Robo2 expression by controlling LIM-domain transcription factors: Gbx2 and Lhx2 compete for binding to the Lmo3 promoter; repressing Lmo3 by Gbx2 is essential for Lhx2 activity to induce Robo2; Gbx2 represses Lhx9 which in turn induces Robo1. TCA-specific reporter, conditional Gbx2 deletion at different embryonic stages, explant culture, mosaic analysis, promoter binding assays Development (Cambridge, England) High 23136391
2012 Gbx2 homeodomain directly binds the TAATTA noncanonical sequence in the Otx2 FM enhancer, competing with class III POU factors (Brn1, Brn2, Brn4, Oct6) for the same target site; Gbx2 misexpression in anterior neural progenitor cells represses FM enhancer activity and inhibits Brn2 association with the enhancer; Gbx2 knockdown causes ectopic Brn2 association in posterior cells, establishing a direct mechanism for Otx2 repression by Gbx2. Chromatin immunoprecipitation, microRNA-mediated knockdown, reporter assays in P19 cells, electrophoretic mobility shift assay Molecular and cellular biology High 22566684
2013 Gbx2 is a direct downstream target of LIF/Stat3 signaling in mouse embryonic stem cells; overexpression of Gbx2 allows long-term mESC self-renewal without LIF/Stat3 signaling; Gbx2 overexpression is sufficient to reprogram epiblast stem cells to ground state ESCs and enhances reprogramming of MEFs to iPSCs. Gain-of-function overexpression, LIF withdrawal assay, epiblast stem cell reprogramming assay Journal of cell science Medium 23345404
2013 Gbx2 functions as a transcriptional repressor in zebrafish; the N-terminal core region including the Eh1 and proline-rich sequences is required for Gbx2 suppressive activity; both N- and C-terminal regions contribute to suppression of anterior brain; a luciferase assay shows gbx2 represses the MHB enhancer of fgf8a; isthmus morphogenesis is highly sensitive to Gbx2 dose. Deletion analysis by mRNA injection in zebrafish, heat-inducible gbx2 transgenic fish, luciferase reporter assay in P19 cells Mechanisms of development High 23933069
2000 Recombinant human GBX2 protein binds specifically to an ATTA motif within the promoter of the interleukin-6 (IL-6) gene; antisense-mediated downregulation of GBX2 in prostate cancer cells decreases IL-6 expression and inhibits tumorigenicity; exogenous IL-6 partially restores growth of antisense GBX2 clones. Gel shift assay with purified recombinant GBX2, antisense knockdown, tumor xenograft assay, rescue with recombinant IL-6 Clinical cancer research : an official journal of the American Association for Cancer Research Medium 10690529
2012 ChIP-Seq analysis identifies GBX2 direct genomic binding targets in a human prostate cancer cell line, including EEF1A1, ROBO1, PLXNA4, SLIT3, NRP1, NOTCH2, PCDH15, and USH2A; gel shift assays confirm direct binding of GBX2 to sequences in promoters/introns of EEF1A1, ROBO1, PCDH15, USH2A, and NOTCH2; GBX2 activates transcription through the EEF1A1 promoter; Gbx2 is required for migration of Robo1-expressing neural crest cells out of the hindbrain. ChIP-Seq, electrophoretic gel shift assay, transcriptional reporter assay, Gbx2 null mouse neural crest analysis PloS one High 23144817
2015 Gbx2 promotes thalamic molecular identity and inhibits habenular molecular characters in the developing thalamus; deletion of Gbx2 changes gene expression and cell proliferation in dividing thalamic progenitors despite Gbx2 being expressed in postmitotic cells; this effect is partially rescued by mosaic wild-type cells, demonstrating a cell-non-autonomous feedback from postmitotic neurons to progenitors. Genome-wide transcriptional profiling, Gbx2 conditional KO, mosaic rescue analysis Developmental biology High 26297811
2017 Gbx2 induces expression of Klf4 (Krüppel-like factor 4) as a direct target; Klf4 mediates the self-renewal-promoting effects of Gbx2 in mouse ESCs; knockdown of Klf4 abrogates Gbx2's ability to maintain undifferentiated mESCs; Gbx2 largely depends on Klf4 to reprogram epiblast stem cells to mESC-like state. RNA-Seq, Klf4 knockdown epistasis, ESC self-renewal and reprogramming assays The Journal of biological chemistry Medium 28848051
2020 Gbx2 is required for cell fate specification and dendritic stratification of specific amacrine cell subtypes in the mouse retina; Gbx2 labels two AC subtypes: a GABAergic subtype receiving On bipolar input, and a non-GABAergic, non-glycinergic subtype with asymmetric dendrites; Gbx2+ nGnG ACs exhibit spatially restricted tracer coupling to bipolar cells through gap junctions. Gbx2CreERT2-IRES-EGFP genetic labeling, RNA-seq, patch-clamp electrophysiology, morphological analysis Cell reports High 33207201
2023 Gbx2 is required for dendritic stratification of a specific amacrine cell subtype in the mouse retina; Robo1 and Robo2 are identified as direct downstream effectors of Gbx2 and when deleted phenocopy Gbx2 mutant dendritic misprojections; Slit1 and Slit2 (Robo ligands) are localized to OFF layers where dendritic misprojections occur in Gbx2 and Robo1/2 mutants, establishing Slit-Robo signaling as the mechanism for ON-OFF pathway segregation downstream of Gbx2. Gbx2 mutant mouse analysis, Robo1/2 conditional KO, dendritic morphology quantification bioRxiv : the preprint server for biologypreprint Medium 37577554
2005 Sef and Sprouty proteins function synergistically as feedback antagonists of FGF signaling to regulate Gbx2 expression in the anterior hindbrain; dominant-negative Sprouty2 electroporation expands or shifts the Gbx2 expression domain, with significantly enhanced effect in Sef mutant background, placing Gbx2 downstream of FGF/Sef/Sprouty signaling. In utero electroporation, Sef homozygous mutant mouse, dominant-negative Sprouty2 in wild-type vs. Sef mutant background Genesis (New York, N.Y. : 2000) Medium 15729686
2020 SNHG6 (stabilized by NCBP3) inhibits GBX2 transcription by mediating H3K27me3 modification induced by polycomb repressive complex 2 (PRC2); GBX2 in turn decreases promoter activity and expression of the FLOT1 oncogene. NCBP3 knockdown, RNA pulldown/RIP, histone modification analysis (H3K27me3 ChIP), promoter activity assay RNA biology Medium 32618493
2006 A threshold level of Gbx2 gene product is required in different regions of the hindbrain: reduced Gbx2 (6-10% of normal) supports r3 but not r2 development; the anterior r1 is converted to isthmus-like tissue with robust Fgf8 and Fgf17 expression and reduced cyclin D2/cellular proliferation, demonstrating Gbx2 dosage controls the r1/isthmus identity boundary. Gbx2 hypomorphic allele (Gbx2neo), quantitative RT-PCR, in situ hybridization, BrdU proliferation analysis Development (Cambridge, England) High 16651541
2009 Persistent misexpression of Gbx2 throughout the mesencephalon (via En1-Cre) largely abolishes Fgf8 expression at the isthmic organizer, leading to deletion of midbrain and cerebellum; juxtaposition of Gbx2 and Otx2 expression domains is essential for maintenance of Fgf8 expression. Conditional gain-of-function transgenic mouse (Gbx2-GOF × En1-Cre), in situ hybridization Genesis (New York, N.Y. : 2000) Medium 19603509
2006 Mutual repression between Gbx2 and Otx2 in the otic vesicle defines the Fgf10 expression domain to induce the cochlear ganglion; ectopic Gbx2 represses Otx2 and vice versa in the chick otic epithelium; Fgf10 expression is repressed by ectopic Gbx2 or Otx2, and cochlear ganglion formation and endolymphatic duct development are disrupted. In ovo electroporation gain-of-function in chick otic vesicle, in situ hybridization Development, growth & differentiation Medium 16961590

Source papers

Stage 0 corpus · 75 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Spatially restricted expression of Dlx-1, Dlx-2 (Tes-1), Gbx-2, and Wnt-3 in the embryonic day 12.5 mouse forebrain defines potential transverse and longitudinal segmental boundaries. The Journal of neuroscience : the official journal of the Society for Neuroscience 523 7687285
1997 Specification of the anterior hindbrain and establishment of a normal mid/hindbrain organizer is dependent on Gbx2 gene function. Development (Cambridge, England) 317 9247335
1999 FGF8 can activate Gbx2 and transform regions of the rostral mouse brain into a hindbrain fate. Development (Cambridge, England) 175 10518499
2001 EN and GBX2 play essential roles downstream of FGF8 in patterning the mouse mid/hindbrain region. Development (Cambridge, England) 133 11124114
2009 The posteriorizing gene Gbx2 is a direct target of Wnt signalling and the earliest factor in neural crest induction. Development (Cambridge, England) 124 19736322
2000 Interaction between Otx2 and Gbx2 defines the organizing center for the optic tectum. Mechanisms of development 121 10704829
2009 Tbx1 controls cardiac neural crest cell migration during arch artery development by regulating Gbx2 expression in the pharyngeal ectoderm. Development (Cambridge, England) 110 19700621
2002 Changing requirements for Gbx2 in development of the cerebellum and maintenance of the mid/hindbrain organizer. Neuron 107 12367504
1995 Sequence and expression pattern of the Stra7 (Gbx-2) homeobox-containing gene induced by retinoic acid in P19 embryonal carcinoma cells. Developmental dynamics : an official publication of the American Association of Anatomists 100 8601031
2001 Regionalisation of anterior neuroectoderm and its competence in responding to forebrain and midbrain inducing activities depend on mutual antagonism between OTX2 and GBX2. Development (Cambridge, England) 99 11731459
2013 Gbx2, a LIF/Stat3 target, promotes reprogramming to and retention of the pluripotent ground state. Journal of cell science 90 23345404
2009 Transcription factor Gbx2 acts cell-nonautonomously to regulate the formation of lineage-restriction boundaries of the thalamus. Development (Cambridge, England) 88 19279136
1997 The homeobox gene GBX2, a target of the myb oncogene, mediates autocrine growth and monocyte differentiation. Cell 86 9346236
2001 Neuroepithelial co-expression of Gbx2 and Otx2 precedes Fgf8 expression in the isthmic organizer. Mechanisms of development 81 11231064
1999 Fgf8 and Gbx2 induction concomitant with Otx2 repression is correlated with midbrain-hindbrain fate of caudal prosencephalon. Development (Cambridge, England) 76 10375509
2005 Gbx2 is required for the morphogenesis of the mouse inner ear: a downstream candidate of hindbrain signaling. Development (Cambridge, England) 75 15829521
2000 Pax2, Otx2, Gbx2 and Fgf8 expression in early otic vesicle development. Mechanisms of development 63 10906468
2005 Specification of the meso-isthmo-cerebellar region: the Otx2/Gbx2 boundary. Brain research. Brain research reviews 57 16111544
2003 Cloning, expression and relationship of zebrafish gbx1 and gbx2 genes to Fgf signaling. Mechanisms of development 57 12963112
1998 Expression of Gbx-2 during early development of the chick embryo. Mechanisms of development 57 9767156
2005 Loss of Gbx2 results in neural crest cell patterning and pharyngeal arch artery defects in the mouse embryo. Developmental biology 56 15996652
2003 gbx2 Homeobox gene is required for the maintenance of the isthmic region in the zebrafish embryonic brain. Developmental dynamics : an official publication of the American Association of Anatomists 51 14579382
2011 Gbx2 and Fgf8 are sequentially required for formation of the midbrain-hindbrain compartment boundary. Development (Cambridge, England) 47 21266408
2010 The mouse homeobox gene Gbx2 is required for the development of cholinergic interneurons in the striatum. The Journal of neuroscience : the official journal of the Society for Neuroscience 47 21048141
1998 Expression of the homeobox gene GBX2 during chicken development. Mechanisms of development 42 9767154
2006 Gbx2 and Otx2 interact with the WD40 domain of Groucho/Tle corepressors. Molecular and cellular biology 41 17060451
2015 Gbx2 is essential for maintaining thalamic neuron identity and repressing habenular characters in the developing thalamus. Developmental biology 39 26297811
2012 Gbx2 regulates thalamocortical axon guidance by modifying the LIM and Robo codes. Development (Cambridge, England) 37 23136391
1997 The mouse homeobox gene, Gbx2: genomic organization and expression in pluripotent cells in vitro and in vivo. Genomics 37 9417909
2007 A phosphomimetic mutation in the Sall1 repression motif disrupts recruitment of the nucleosome remodeling and deacetylase complex and repression of Gbx2. The Journal of biological chemistry 36 17895244
2005 Synergistic activity of Sef and Sprouty proteins in regulating the expression of Gbx2 in the mid-hindbrain region. Genesis (New York, N.Y. : 2000) 36 15729686
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
2006 A threshold requirement for Gbx2 levels in hindbrain development. Development (Cambridge, England) 32 16651541
2002 Gbx2 expression in the late embryonic chick dorsal thalamus. Brain research bulletin 31 11923005
2002 Gbx2 interacts with Otx2 and patterns the anterior-posterior axis during gastrulation in Xenopus. Mechanisms of development 30 11850185
2002 Differential expression of Otx2, Gbx2, Pax2, and Fgf8 in the developing vestibular and auditory sensory organs. Brain research bulletin 29 11922981
2000 Enhanced GBX2 expression stimulates growth of human prostate cancer cells via transcriptional up-regulation of the interleukin 6 gene. Clinical cancer research : an official journal of the American Association for Cancer Research 28 10690529
1995 Sequence and evolutionary conservation of the murine Gbx-2 homeobox gene. FEBS letters 27 7758585
1998 Down-regulation of homeobox gene GBX2 expression inhibits human prostate cancer clonogenic ability and tumorigenicity. Cancer research 26 9537237
2012 Gbx2 directly restricts Otx2 expression to forebrain and midbrain, competing with class III POU factors. Molecular and cellular biology 24 22566684
2013 Gbx2 functions as a transcriptional repressor to regulate the specification and morphogenesis of the mid-hindbrain junction in a dosage- and stage-dependent manner. Mechanisms of development 21 23933069
2018 MicroRNA-4497 functions as a tumor suppressor in laryngeal squamous cell carcinoma via negatively modulation the GBX2. Auris, nasus, larynx 19 29843929
2017 The transcription factor Gbx2 induces expression of Kruppel-like factor 4 to maintain and induce naïve pluripotency of embryonic stem cells. The Journal of biological chemistry 19 28848051
2012 Gbx2 plays an essential but transient role in the formation of thalamic nuclei. PloS one 19 23056596
2011 The lineage contribution and role of Gbx2 in spinal cord development. PloS one 19 21698205
2020 Gbx2 Identifies Two Amacrine Cell Subtypes with Distinct Molecular, Morphological, and Physiological Properties. Cell reports 18 33207201
2005 New regulatory interactions and cellular responses in the isthmic organizer region revealed by altering Gbx2 expression. Development (Cambridge, England) 18 15790971
2020 NCBP3/SNHG6 inhibits GBX2 transcription in a histone modification manner to facilitate the malignant biological behaviour of glioma cells. RNA biology 17 32618493
1996 Expression of homeobox gene-GBX2 in human prostatic cancer cells. The Prostate 17 8977637
2002 The expression of gbx-2 during zebrafish embryogenesis. Mechanisms of development 16 11900984
2001 The two Xenopus Gbx2 genes exhibit similar, but not identical expression patterns and can affect head formation. FEBS letters 15 11684099
1996 Characterization and sequence analysis of the human homeobox-containing gene GBX2. Genomics 15 8838315
2022 circRERE regulates the expression of GBX2 through miR-1299 and ZC3H13/N6-methyladenosine (m6A) to promote growth and invasion of hepatocellular carcinoma cells. Journal of biosciences 14 36222159
2009 Misexpression of Gbx2 throughout the mesencephalon by a conditional gain-of-function transgene leads to deletion of the midbrain and cerebellum in mice. Genesis (New York, N.Y. : 2000) 14 19603509
2006 Role of Gbx2 and Otx2 in the formation of cochlear ganglion and endolymphatic duct. Development, growth & differentiation 14 16961590
2017 Comprehensive analysis of target genes in zebrafish embryos reveals gbx2 involvement in neurogenesis. Developmental biology 13 28756106
2012 Elongation factor 1 alpha1 and genes associated with Usher syndromes are downstream targets of GBX2. PloS one 13 23144817
2011 Evolutionarily conserved function of Gbx2 in anterior hindbrain development. Developmental dynamics : an official publication of the American Association of Anatomists 13 21360792
2020 Pax9 and Gbx2 Interact in the Pharyngeal Endoderm to Control Cardiovascular Development. Journal of cardiovascular development and disease 12 32466118
2018 Downregulated GBX2 gene suppresses proliferation, invasion and angiogenesis of breast cancer cells through inhibiting the Wnt/β-catenin signaling pathway. Cancer biomarkers : section A of Disease markers 12 30223390
2013 MRI analysis of cerebellar and vestibular developmental phenotypes in Gbx2 conditional knockout mice. Magnetic resonance in medicine 12 23400959
2017 The role of gastrulation brain homeobox 2 (gbx2) in the development of the ventral telencephalon in zebrafish embryos. Differentiation; research in biological diversity 10 29289755
2016 Directional cell movements downstream of Gbx2 and Otx2 control the assembly of sensory placodes. Biology open 10 27659690
2021 LncRNA FEZF1-AS1 accelerates the migration and invasion of laryngeal squamous cell carcinoma cells through miR-4497 targeting GBX2. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery 8 33550476
2020 Gbx1 and Gbx2 Are Essential for Normal Patterning and Development of Interneurons and Motor Neurons in the Embryonic Spinal Cord. Journal of developmental biology 8 32244588
2022 Oncogenic GBX2 promotes the malignant behaviors of bladder cancer cells by binding to the ITGA5 promoter and activating its transcription. Functional & integrative genomics 7 35672622
2019 GBX2, as a tumor promoter in lung adenocarcinoma, enhances cells viability, invasion and migration by regulating the AKT/ERK signaling pathway. The journal of gene medicine 6 31758726
2020 Gbx2 Is Required for the Migration and Survival of a Subpopulation of Trigeminal Cranial Neural Crest Cells. Journal of developmental biology 4 33322598
2017 The Temporal Contribution of the Gbx2 Lineage to Cerebellar Neurons. Frontiers in neuroanatomy 4 28785208
2023 Gbx2 controls amacrine cell dendrite stratification through Robo1/2 receptors. bioRxiv : the preprint server for biology 2 37577554
2018 The N-terminal domain of gastrulation brain homeobox 2 (Gbx2) is required for iridophore specification in zebrafish. Biochemical and biophysical research communications 2 29787751
2024 hsa_circ_0021727 facilitates esophageal squamous cell carcinoma progression by stabilizing GBX2 mRNA through interacting with EIF4A3. Neoplasma 1 39832205
2018 4D imaging identifies dynamic migration and the fate of gbx2-expressing cells in the brain primordium of zebrafish. Neuroscience letters 1 30222999
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2026 The ultra-conserved lncRNA Crnde regulates neural differentiation by targeting Gbx2 during embryonic development of the thalamus. Journal of genetics and genomics = Yi chuan xue bao 0 41655632