Affinage

GLI3

Transcriptional activator GLI3 · UniProt P10071

Length
1580 aa
Mass
169.9 kDa
Annotated
2026-04-28
100 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GLI3 is a bifunctional zinc-finger transcription factor that serves as the principal effector of Hedgehog (Hh) signaling in vertebrate development, toggling between a full-length transcriptional activator (Gli3A) and a proteolytically processed repressor (Gli3R) to control digit patterning, cortical neurogenesis, renal morphogenesis, and muscle stem cell quiescence (PMID:12198547, PMID:21525285, PMID:16396903, PMID:35803939). Processing to Gli3R requires proteasomal partial degradation directed by a tripartite signal (zinc finger domain, linker, degron), facilitated by PKA phosphorylation at primary cilia and a Sufu/GSK3β complex, while Shh signaling blocks processing to allow Gli3A to accumulate and recruit Mediator (via MED12) and CBP/p300 to activate targets including PTCH1, Gli1, Cdk6, and Wnt5a (PMID:21921029, PMID:19622347, PMID:28673820, PMID:17000779, PMID:30093555, PMID:31550480). Gli3A is further regulated by Set7-mediated methylation that stabilizes the protein and enhances DNA binding, and by SPOP-mediated ubiquitination that promotes its degradation; cancer-associated SPOP mutations stabilize GLI3, enabling cooperation with androgen receptor in prostate cancer (PMID:27146893, PMID:34610962). Heterozygous loss-of-function mutations cause Greig cephalopolysyndactyly syndrome (GCPS), while truncating mutations producing a constitutive repressor cause Pallister–Hall syndrome (PHS), as demonstrated by knock-in mouse models (PMID:10077605, PMID:11978771).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1990 High

    Establishing that GLI3 encodes a zinc-finger protein capable of sequence-specific DNA binding resolved the molecular identity of the gene and placed it in the GLI family of transcription factors.

    Evidence cDNA cloning with in vitro translation and DNA-binding assay

    PMID:2118997

    Open questions at the time
    • No in vivo target genes identified
    • Activator vs. repressor function not yet distinguished
    • No link to signaling pathway
  2. 1992 High

    Demonstrating that Gli3 is the gene disrupted in the extra-toes (Xt) mouse mutant connected its molecular identity to a concrete developmental phenotype affecting limb and brain.

    Evidence Northern blot, RNase protection, and in situ hybridization in Xt/+ and Xt/Xt mice

    PMID:1289066

    Open questions at the time
    • Mechanism of limb/brain defect not resolved
    • No protein-level analysis
  3. 1996 High

    Positioning GLI3 downstream of Sonic hedgehog signaling established the pathway context: Shh down-regulates Gli3 expression while GLI activates Patched, linking vertebrate Hh signaling to GLI-family transcription factors.

    Evidence In situ hybridization and retroviral gain-of-function in chick limb bud with reporter assays

    PMID:8948590

    Open questions at the time
    • Post-translational processing not yet discovered
    • Repressor form not distinguished from transcriptional downregulation
  4. 1999 High

    Discovery that full-length GLI3 is a cytoplasmic activator of PTCH1 while disease-associated truncations produce a nuclear repressor established the bifunctional activator/repressor paradigm and linked it to Pallister–Hall and Greig syndromes.

    Evidence Immunofluorescence localization and PTCH1 promoter-reporter assays with disease-mimicking mutants

    PMID:10077605 PMID:10441342

    Open questions at the time
    • Endogenous processing mechanism unknown
    • Proteasomal involvement not yet shown
    • In vivo repressor function not demonstrated
  5. 2002 High

    Genetic epistasis in Shh;Gli3 double-knockout mice and PHS-mimicking knock-in mice proved that Shh patterns the limb primarily by counteracting Gli3 repressor, and that truncated Gli3 is a constitutive repressor in vivo.

    Evidence Mouse compound knockout and targeted truncation mutation with skeletal phenotyping

    PMID:11978771 PMID:12198547

    Open questions at the time
    • Biochemical basis of processing not resolved
    • Target genes of Gli3R in limb not identified
  6. 2006 High

    ChIP demonstration that Gli3R directly occupies target promoters (Pax2, Sall1, cyclin D1, MYCN, Gli1) in the absence of Shh, and identification of MED12/CBP as coactivators recruited by Gli3A, defined the transcriptional mechanism at both ends of the activator-repressor switch.

    Evidence Chromatin immunoprecipitation in embryonic kidney; Co-IP and GST pulldown of GLI3-MED12 and GLI3-CBP with reporter assays

    PMID:16396903 PMID:17000779

    Open questions at the time
    • Genome-wide binding profile not determined
    • How Gli3R represses without HDACs not fully resolved
  7. 2009 High

    Identification of the Sufu/GSK3β trimolecular complex that phosphorylates Gli3 to enable processing, and the finding that Shh dissociates this complex, provided a biochemical mechanism for pathway-regulated generation of Gli3R.

    Evidence Co-immunoprecipitation in wild-type and Sufu−/− MEFs with processing assays

    PMID:19622347

    Open questions at the time
    • Exact phosphorylation sites for GSK3β on Gli3 not mapped in this study
    • Role of PKA priming phosphorylation not integrated
  8. 2011 High

    Reconstitution of proteasomal processing revealed a tripartite processing signal (zinc finger fold, low-complexity linker, degron) intrinsic to Gli3, explaining why Gli1 escapes processing despite sequence homology.

    Evidence In vitro proteasome processing assay with systematic domain deletion and mutagenesis

    PMID:21921029

    Open questions at the time
    • Structural basis of processing determinant not resolved
    • E3 ligase(s) delivering Gli3 to the proteasome for processing not identified here
  9. 2012 High

    Linking Gli3 processing in primary cilia to cortical progenitor cell cycle length (via cyclin D1 and Fgf15) extended the Gli3R paradigm beyond limb patterning to brain development, and revealed a non-canonical role for Gli3A in KRAS-induced autophagy via VMP1/p300.

    Evidence Conditional Kif3a/Gli3 KO with cell cycle kinetics; ChIP of GLI3 at VMP1 promoter with Co-IP of GLI3-p300

    PMID:21976438 PMID:22535956

    Open questions at the time
    • Hedgehog-independent regulation of GLI3A activity in autophagy not fully characterized
    • Relative contributions of Gli3A vs. Gli3R in cortex not quantitatively resolved
  10. 2016 High

    Set7-mediated methylation at K436 and K595 was shown to stabilize Gli3A protein and enhance its DNA binding, revealing a post-translational activation mechanism that fine-tunes Gli3 activator output independently of processing.

    Evidence In vitro methylation assay, site-directed mutagenesis, cycloheximide chase, DNA-binding and reporter assays

    PMID:27146893

    Open questions at the time
    • Physiological contexts where Set7 regulates Gli3 not broadly mapped
    • Interplay between methylation and other PTMs (phosphorylation, ubiquitination) not resolved
  11. 2017 High

    Demonstration that PKA localizes to centrioles via Talpid3-PKARIIβ interaction and that Hh inhibits PKA-mediated Gli3 phosphorylation at cilia established the spatial logic of Gli3 processing regulation within the cilium.

    Evidence Co-IP of Talpid3-PKARIIβ, immunofluorescence localization, phosphorylation and processing assays in mutant cells

    PMID:28673820

    Open questions at the time
    • Direct measurement of ciliary PKA activity changes upon Hh stimulation not shown
    • Whether all PKA-dependent Gli3 phosphorylation occurs at cilia not established
  12. 2018 High

    ChIP identification of Cdk6 as a direct Gli3 target in cortical progenitors, with pharmacological rescue of the Gli3 mutant phenotype by Cdk6 inhibition, established a precise transcriptional mechanism linking Gli3 to cell cycle control in neurogenesis.

    Evidence Conditional KO, ChIP at Cdk6 locus, pharmacological Cdk6 inhibitor rescue

    PMID:30093555

    Open questions at the time
    • Whether Gli3A or Gli3R binds the Cdk6 promoter not definitively resolved
    • Other direct cell cycle targets not comprehensively identified
  13. 2019 High

    Identification of Wnt5a as a direct co-regulated target of Gli3A and Trps1 during chondrocyte hypertrophy, and of Gli3A as a driver of fetal Leydig cell identity, broadened the activator's known target repertoire and tissue contexts.

    Evidence ChIP of Gli3A and Trps1 at Wnt5a promoter with compound mutant validation; lentiviral GLI3A rescue in Gli3Xt/Xt testes

    PMID:31550480 PMID:32497091

    Open questions at the time
    • Full Gli3A cistrome in these tissues not determined
    • How Trps1 selectively binds Gli3A but not Gli3R structurally unexplained
  14. 2021 High

    Demonstrating that SPOP-mediated ubiquitination degrades Gli3 and that cancer-driver SPOP mutations stabilize Gli3 to cooperate with androgen receptor revealed a pathological consequence of disrupted Gli3 turnover in prostate cancer.

    Evidence Co-IP of GLI3-AR, SPOP-dependent degradation assays with cancer mutants, xenograft tumor models

    PMID:34610962

    Open questions at the time
    • Whether Gli3A or both isoforms are SPOP substrates not fully clarified
    • GLI3-AR co-target genes not comprehensively identified
  15. 2022 High

    Conditional knockout in satellite cells showed that Gli3R processed in primary cilia suppresses mTORC1 to maintain G0 dormancy, extending the Gli3 paradigm to adult stem cell quiescence regulation.

    Evidence Satellite cell-specific conditional Gli3 KO with mTORC1 immunoblotting, single-cell cycle analysis, regeneration assays

    PMID:35803939

    Open questions at the time
    • Direct transcriptional targets of Gli3R that suppress mTORC1 not identified
    • Whether pharmacological Hh modulation can toggle satellite cell states via Gli3 not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A genome-wide map of Gli3A and Gli3R binding sites across tissues, the structural basis for proteasomal partial processing, and the integration of multiple post-translational inputs (PKA, GSK3β, Set7, SPOP, PP2A/MID1) into a quantitative model of Gli3 activator-repressor balance remain unresolved.
  • No genome-wide ChIP-seq across multiple tissues distinguishing Gli3A from Gli3R occupancy
  • Structural mechanism of proteasomal partial processing not solved
  • Quantitative integration of competing PTMs on Gli3 not modeled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 9 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 3 GO:0005929 cilium 3 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1266738 Developmental Biology 4 R-HSA-1640170 Cell Cycle 3
Partners
ARCREBBPGSK3BMED12MID1SPOPSUFUTRPS1
Complex memberships
Gli3/Sufu/GSK3β processing complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 GLI3 encodes a 190 kDa protein with seven regions of similarity to GLI (53–88% identity), with zinc fingers as the most similar region; the GLI3 protein produced in vitro binds specifically to genomic DNA fragments containing GLI-binding sites, establishing it as a sequence-specific DNA-binding transcription factor. cDNA cloning, in vitro translation, DNA-binding assay Molecular and cellular biology High 2118997
1992 Gli3 expression is reduced ~50% in heterozygous Xt/+ mice and completely absent in homozygous Xt/Xt mice, with expression detected in developing limb and brain — structures affected in the mutant — establishing Gli3 as the gene disrupted in the extra-toes mouse mutant. Northern blot, RNase protection assay, in situ hybridization Development (Cambridge, England) High 1289066
1996 Sonic hedgehog differentially regulates GLI family members: it up-regulates GLI1 transcription while down-regulating GLI3 expression in limb bud mesenchyme; an activated form of GLI can induce Patched expression, placing GLI/GLI3 downstream of Shh in vertebrate hedgehog signaling. In situ hybridization, retroviral gain-of-function in chick limb bud, reporter assay Developmental biology High 8948590
1999 Full-length GLI3 localizes to the cytoplasm and activates PTCH1 expression (analogous to full-length Ci155); a PHS truncation mutant localizes to the nucleus and represses GLI3-activated PTCH1 expression (analogous to Ci75 repressor); GCPS mutants have no effect on PTCH1 transactivation, consistent with haploinsufficiency. This established that GLI3 undergoes nuclear/cytoplasmic partitioning and has both activator and repressor forms. Subcellular localization by immunofluorescence, reporter gene (PTCH1 promoter) transfection assays, site-directed mutagenesis reflecting disease mutations Proceedings of the National Academy of Sciences of the United States of America High 10077605
1999 Transactivation capacity of GLI3 was mapped to two independent adjacent activation domains (TA1 and TA2) in the C-terminal third of the protein, defined by cell transfection experiments using GAL4-GLI3 fusion proteins covering different segments. GAL4-fusion reporter transfection assays in cell culture Human molecular genetics Medium 10441342
2002 Genetic analysis in Shh−/−;Gli3−/− double-mutant mice shows that Shh and Gli3 are dispensable for limb skeletal element formation, but their interaction is required for digit number and identity. The effects of Shh on skeletal patterning are necessarily mediated through Gli3, establishing Gli3 as the primary downstream effector of Shh in limb patterning. Genetic epistasis; mouse double-knockout analysis with skeletal phenotyping Nature High 12198547
2002 A targeted truncating mutation in mice mimicking the PHS mutation (removing sequences 3′ of the zinc-finger domain) causes central polydactyly and a full spectrum of PHS features, demonstrating that the truncated GLI3 protein acts as a constitutive repressor in vivo. Targeted gene mutation in mice, phenotypic characterization Human molecular genetics High 11978771
2004 Elevated Gli3 repressor levels (due to absence of Shh signaling) correlate with increased Bmp4 expression and apoptosis in the developing limb; exogenous Noggin prevents this apoptosis, indicating that Gli3R promotes BMP4-mediated cell death in a position-dependent manner. Posterior wing bud removal assay, protein immunodetection, bead implantation, Noggin application Developmental dynamics Medium 15305295
2006 GLI3 physically interacts with MED12, a subunit of the RNA Pol II Mediator complex, through a transactivation domain (MBD); this interaction, together with histone acetyltransferase CBP, is required for Gli3-dependent transcriptional activation of Shh target genes. Dominant-negative interference with the Gli3-MED12 interaction inhibits, while MED12 RNAi enhances, both MBD transactivation and Gli3 target gene induction. Co-immunoprecipitation in vitro and in vivo, GST pulldown, reporter assays, RNAi, dominant-negative overexpression Molecular and cellular biology High 17000779
2006 GLI3-dependent transcriptional repression controls renal morphogenesis: in the absence of Shh-SMO signaling, GLI3 repressor binds to Shh target gene promoters (Pax2, Sall1, cyclin D1, MYCN, Gli1, Gli2) via chromatin immunoprecipitation, replacing GLI1/GLI2 activators; elimination of Gli3 in Shh−/− mice rescues kidney malformation. Chromatin immunoprecipitation (ChIP), genetic epistasis (Gli3;Shh double mutants), embryonic kidney explants with cyclopamine, protein immunoblotting Development (Cambridge, England) High 16396903
2007 Canonical Wnt/β-catenin/Tcf signaling directly regulates Gli3 expression through conserved Tcf-binding sequences in non-coding DNA regions around the GLI3 gene; dorsal Gli3 expression in the neural tube is directly controlled by Wnt1/Wnt3a, and Gli3 in turn represses ventral Shh/Gli activity to pattern the spinal cord. Conserved non-coding DNA characterization, reporter assays (Tcf binding sites), in vivo gain/loss-of-function in chick neural tube Development (Cambridge, England) Medium 18057099
2008 Identification of a minimal transcriptional repressor domain within GLI3 mapped to residues 106–236 in the N-terminal half; this domain does not utilize histone deacetylases (HDACs) to achieve repression, as demonstrated by HDAC inhibitor treatment and pulldown assays. Overexpression reporter assays, HDAC inhibitor treatment, pulldown assays, deletion mapping FEBS letters Medium 19084012
2009 Sufu recruits GSK3β to form a trimolecular Gli3/Sufu/GSK3β complex that mediates phosphorylation of Gli3 by GSK3β, which is essential for Gli3 proteolytic processing to generate the transcriptional repressor form. Sonic Hh stimulation dissociates the Sufu/GSK3β complex from Gli3, blocking processing. Co-immunoprecipitation (Sufu-GSK3β, Sufu-Gli3), Sufu−/− MEFs and siRNA knockdown showing loss of processing, immunoblotting for Gli3 processing Biochemical and biophysical research communications High 19622347
2009 Trps1 specifically binds the transactivation domain of the full-length (activator) form of Gli3 in vitro and in vivo; the repressor form of Gli3 does not interact with Trps1. A 185-aa domain of Trps1 containing three predicted zinc fingers is sufficient for the interaction. Co-immunoprecipitation in vivo, in vitro binding assay, domain mapping with deletion constructs, compound mouse mutant analysis Developmental biology High 19389374
2009 PP2A and the ubiquitin ligase MID1 regulate the nuclear localization and transcriptional activity of GLI3; functional interaction between the MID1-α4-PP2A complex and GLI3 was mapped to amino acids 568–1100 of GLI3; GCPS-associated point mutations in this region lead to misregulation of GLI3 subcellular localization and transcriptional activity. Co-immunoprecipitation, deletion mapping, subcellular localization by immunofluorescence, reporter assays, GCPS disease mutations PloS one Medium 19829694
2011 Gli3 repressor (Gli3R) is required for specifying the fate of cortical neurons in temporal order and for maintaining cortical progenitors in active cell cycle; conditional deletion of Gli3 after patterning causes progenitors to exit the cell cycle prematurely, establishing a direct role for Gli3R in cortical neurogenesis. Conditional mouse knockout, birthdating experiments, in utero electroporation, cell cycle analysis The Journal of neuroscience High 21525285
2011 Proteasome-mediated partial degradation (processing) of Gli3 requires a three-part signal: the zinc finger domain (as a folded structure), an adjacent linker sequence containing regions of low complexity, and a degron. Gli1 is not processed because its linker sequence and degron are ineffective, despite overall homology. In vitro proteasome processing assays, domain deletion and mutagenesis, cell-based reporter The Journal of biological chemistry High 21921029
2012 GLI3 binds to the VMP1 promoter and complexes with histone acetyltransferase p300 to regulate VMP1 promoter activity, mediating KRAS-induced autophagy downstream of the PI3K-AKT1 pathway in a Hedgehog-independent manner; GLI3 knockdown impairs autophagy and VMP1 expression. Chromatin immunoprecipitation (GLI3 at VMP1 promoter), Co-IP (GLI3-p300), RNAi knockdown, promoter-reporter assays The Journal of biological chemistry High 22535956
2012 Loss of primary cilia (via Kif3a deletion) or Gli3 alone reduces Gli3 repressor activity and increases cyclin D1 and Fgf15 expression, shortening the G1 phase and causing cortical overgrowth; levels of full-length and repressor Gli3 are tightly regulated during normal cortical development, establishing that primary cilia regulate Gli3 processing to control cortical progenitor cell cycle length. Conditional Kif3a KO, Gli3 KO, immunoblotting for Gli3 isoforms, cell cycle kinetics measurement, qPCR for target genes Developmental neurobiology High 21976438
2016 Set7 (a lysine methyltransferase) methylates full-length GLI3 at K436 and K595; methylation at K436 increases Gli3 protein stability, and methylation at K595 increases DNA-binding ability, both enhancing Shh signaling activation. The truncated/repressor form of Gli3 is not methylated. In vitro methylation assay, site-directed mutagenesis (K436A, K595A), protein stability assay (cycloheximide chase), DNA-binding assay, reporter assays, xenograft tumor models eLife High 27146893
2016 miR-378a-3p directly targets the Gli3 3′UTR; overexpression of miR-378a-3p reduces Gli3 expression in activated hepatic stellate cells (HSCs) and suppresses profibrotic gene expression; Smo blocks miR-378a-3p transcription via p65 NF-κB activation, revealing an Smo-NF-κB-miR-378a-3p-Gli3 regulatory axis in liver fibrosis. miRNA target validation (luciferase reporter), miRNA overexpression and inhibition in HSCs, in vivo CCl4 model, NF-κB ChIP/reporter Nature communications High 27001906
2017 Hedgehog signaling inhibits PKA-mediated phosphorylation of Gli2 and Gli3 in primary cilia; the Talpid3 centriolar protein interacts with PKA regulatory subunit PKARIIβ at centrioles, and loss of Talpid3 reduces PKARIIβ centriolar localization, resulting in reduced Gli2/Gli3 phosphorylation and impaired processing to repressor forms. Co-immunoprecipitation (Talpid3-PKARIIβ), immunofluorescence localization, phosphorylation analysis by immunoblot, Gli3 processing assay in mutant cells Developmental biology High 28673820
2017 Spop (an E3 ubiquitin ligase adaptor) negatively regulates the level and activator activity of Gli3 in spinal cord patterning; loss of Spop increases Gli3 protein levels and suppresses floor plate/V3 interneuron loss in Gli2 mutants by enhancing Gli3 activator function. Genetic epistasis (Spop;Gli2 double mutants, Spop;Gli1;Sufu triple mutants), quantitative immunoblotting of Gli3 protein levels Developmental biology Medium 28412462
2018 Gli3 controls the onset of cortical neurogenesis by directly regulating Cdk6 expression, thereby setting G1 and S phase length in radial glial cells; pharmacological Cdk6 inhibition rescues the delayed neurogenesis seen in Gli3 conditional mutants. Conditional mouse KO, gene expression profiling, cell cycle measurements, ChIP (Gli3 at Cdk6 locus), pharmacological rescue with Cdk6 inhibitor Development (Cambridge, England) High 30093555
2019 Gli3 activator (GLI3A) in fetal Leydig cells promotes their identity and stimulates INSL3 and testosterone synthesis; reintroduction of GLI3A into Gli3Xt/Xt testes restores Hedgehog pathway and steroidogenic gene expression, establishing a novel function for the activated form of GLI3 in translating Hedgehog signals to reinforce Leydig cell identity. Gli3XtJ mouse mutant analysis, androgen supplementation rescue, lentiviral GLI3A reintroduction, gene expression profiling PLoS genetics High 32497091
2019 Trps1 and the activator form of Gli3 (Gli3A) directly bind two upstream regulatory sequences in the Wnt5a promoter (identified by ChIP and reporter assays) to activate Wnt5a expression at the onset of chondrocyte hypertrophy; loss of both factors decreases endogenous Wnt5a mRNA and protein levels. Chromatin immunoprecipitation (Trps1 and Gli3A at Wnt5a promoter), reporter gene assays, compound mouse mutant analysis, qRT-PCR and Western blot Developmental biology High 31550480
2021 GLI3 is a substrate of SPOP-mediated proteasomal degradation; cancer-driver mutations in SPOP abrogate GLI3 degradation and stabilize GLI3 protein. Stabilized GLI3 physically interacts with androgen receptor (AR) and functionally cooperates with it to drive an AR-dependent gene expression program supporting castration-resistant prostate cancer growth. Co-immunoprecipitation (GLI3-AR), proteasomal degradation assays (SPOP mutants), xenograft tumor models, gene expression analysis Molecular cancer research High 34610962
2022 GLI3 processing by the primary cilium maintains satellite cells in G0 dormancy by suppressing mTORC1 signaling; loss of GLI3 activates mTORC1, driving satellite cells into GAlert and enhancing proliferation, self-renewal, and regenerative capacity without injury. Conditional satellite cell-specific Gli3 KO, mTORC1 signaling immunoblotting, single-cell cycle analysis, regeneration assays Nature communications High 35803939

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 The hem of the embryonic cerebral cortex is defined by the expression of multiple Wnt genes and is compromised in Gli3-deficient mice. Development (Cambridge, England) 493 9584130
2002 Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature 470 12198547
1998 Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus. Nature genetics 439 9731531
1996 Sonic hedgehog differentially regulates expression of GLI and GLI3 during limb development. Developmental biology 327 8948590
1998 The Shh signalling pathway in tooth development: defects in Gli2 and Gli3 mutants. Development (Cambridge, England) 294 9655803
1997 Haploinsufficient phenotypes in Bmp4 heterozygous null mice and modification by mutations in Gli3 and Alx4. Developmental biology 243 9268572
2016 MicroRNA-378 limits activation of hepatic stellate cells and liver fibrosis by suppressing Gli3 expression. Nature communications 183 27001906
2007 Wnt canonical pathway restricts graded Shh/Gli patterning activity through the regulation of Gli3 expression. Development (Cambridge, England) 160 18057099
1990 GLI3 encodes a 190-kilodalton protein with multiple regions of GLI similarity. Molecular and cellular biology 158 2118997
2002 Pallister-Hall syndrome phenotype in mice mutant for Gli3. Human molecular genetics 152 11978771
2006 GLI3-dependent transcriptional repression of Gli1, Gli2 and kidney patterning genes disrupts renal morphogenesis. Development (Cambridge, England) 148 16396903
1992 Expression of the zinc finger gene Gli3 is affected in the morphogenetic mouse mutant extra-toes (Xt). Development (Cambridge, England) 146 1289066
1999 GLI3 mutations in human disorders mimic Drosophila cubitus interruptus protein functions and localization. Proceedings of the National Academy of Sciences of the United States of America 142 10077605
1997 Point mutations in human GLI3 cause Greig syndrome. Human molecular genetics 141 9302279
1984 Nucleotide sequence of the papA gene encoding the Pap pilus subunit of human uropathogenic Escherichia coli. Journal of bacteriology 138 6140260
2004 Gli2 and Gli3 have redundant and context-dependent function in skeletal muscle formation. Development (Cambridge, England) 128 15604102
2010 Clinical, Molecular, and Genetic Characteristics of PAPA Syndrome: A Review. Current genomics 127 21532836
2003 Interplays of Gli2 and Gli3 and their requirement in mediating Shh-dependent sclerotome induction. Development (Cambridge, England) 123 14602680
1999 Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome. Human molecular genetics 118 10441342
2003 A disrupted balance between Bmp/Wnt and Fgf signaling underlies the ventralization of the Gli3 mutant telencephalon. Developmental biology 107 12921747
2006 Mediator modulates Gli3-dependent Sonic hedgehog signaling. Molecular and cellular biology 106 17000779
2020 GLI3: a mediator of genetic diseases, development and cancer. Cell communication and signaling : CCS 101 32245491
2017 PAPA, PASH and PAPASH Syndromes: Pathophysiology, Presentation and Treatment. American journal of clinical dermatology 91 28236224
2003 Differential requirement for Gli2 and Gli3 in ventral neural cell fate specification. Developmental biology 91 12812795
2000 Regulatory cross-talk between adhesin operons in Escherichia coli: inhibition of type 1 fimbriae expression by the PapB protein. The EMBO journal 89 10747013
2005 Zebrafish Gli3 functions as both an activator and a repressor in Hedgehog signaling. Developmental biology 87 15617692
2014 New insights into genotype-phenotype correlation for GLI3 mutations. European journal of human genetics : EJHG 85 24736735
2018 Dysregulated neutrophil responses and neutrophil extracellular trap formation and degradation in PAPA syndrome. Annals of the rheumatic diseases 81 30131320
2009 Trps1, a regulator of chondrocyte proliferation and differentiation, interacts with the activator form of Gli3. Developmental biology 81 19389374
2009 Sufu recruits GSK3beta for efficient processing of Gli3. Biochemical and biophysical research communications 81 19622347
2005 Pax9 and Jagged1 act downstream of Gli3 in vertebrate limb development. Mechanisms of development 81 16169709
2017 GLI3 repressor determines Hedgehog pathway activation and is required for response to SMO antagonist glasdegib in AML. Blood 68 28487292
2012 Primary cilia and Gli3 activity regulate cerebral cortical size. Developmental neurobiology 68 21976438
2006 Peculiarities of PAPA syndrome. Rheumatology (Oxford, England) 66 16527883
2006 What you can learn from one gene: GLI3. Journal of medical genetics 66 16740916
1993 PAP, a pancreatic secretory protein induced during acute pancreatitis, is expressed in rat intestine. The American journal of physiology 66 8238345
2016 MiRNA-133b promotes the proliferation of human Sertoli cells through targeting GLI3. Oncotarget 65 26755652
2011 Gli3 is required for maintenance and fate specification of cortical progenitors. The Journal of neuroscience : the official journal of the Society for Neuroscience 65 21525285
2007 Kinesin-2 controls development and patterning of the vertebrate skeleton by Hedgehog- and Gli3-dependent mechanisms. Developmental biology 62 17698054
2012 Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells. The Journal of biological chemistry 60 22535956
2016 Set7 mediated Gli3 methylation plays a positive role in the activation of Sonic Hedgehog pathway in mammals. eLife 56 27146893
2015 Sox2, Tlx, Gli3, and Her9 converge on Rx2 to define retinal stem cells in vivo. The EMBO journal 52 25908840
2005 The transcription factor Gli3 regulates differentiation of fetal CD4- CD8- double-negative thymocytes. Blood 50 15855276
2004 Levels of Gli3 repressor correlate with Bmp4 expression and apoptosis during limb development. Developmental dynamics : an official publication of the American Association of Anatomists 49 15305295
2009 The Hedgehog transcription factor Gli3 modulates angiogenesis. Circulation research 48 19729595
2008 A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy. Human molecular genetics 48 18397875
2013 Sost and its paralog Sostdc1 coordinate digit number in a Gli3-dependent manner. Developmental biology 47 23994639
2017 GLI3-related polydactyly: a review. Clinical genetics 46 28224613
2006 Abnormal positioning of diencephalic cell types in neocortical tissue in the dorsal telencephalon of mice lacking functional Gli3. The Journal of neuroscience : the official journal of the Society for Neuroscience 46 16957084
2005 Gli3 is required for the specification and differentiation of preplate neurons. Developmental biology 43 16168404
2009 A SHH-independent regulation of Gli3 is a significant determinant of anteroposterior patterning of the limb bud. Developmental biology 42 19248778
2014 Cytogenetic and morphologic approaches of hybrids from experimental crosses between Triatoma lenti Sherlock & Serafim, 1967 and T. sherlocki Papa et al., 2002 (Hemiptera: Reduviidae). Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 39 24861813
2018 miR-7-5p acts as a tumor suppressor in bladder cancer by regulating the hedgehog pathway factor Gli3. Biochemical and biophysical research communications 36 30100065
2012 Haplotype distribution in the GLI3 gene and their associations with growth traits in cattle. Gene 36 23142388
2007 Nonsense-mediated decay and the molecular pathogenesis of mutations in SALL1 and GLI3. American journal of medical genetics. Part A 36 18000979
2022 GLI3 regulates muscle stem cell entry into GAlert and self-renewal. Nature communications 35 35803939
2019 Gli3 Regulates Vomeronasal Neurogenesis, Olfactory Ensheathing Cell Formation, and GnRH-1 Neuronal Migration. The Journal of neuroscience : the official journal of the Society for Neuroscience 35 31767679
2007 Ultraconserved non-coding sequence element controls a subset of spatiotemporal GLI3 expression. Development, growth & differentiation 35 17661744
2015 Sonic hedgehog through Gli2 and Gli3 is required for the proper development of placental labyrinth. Cell death & disease 32 25695606
2012 Expanded mutational spectrum of the GLI3 gene substantiates genotype-phenotype correlations. Journal of applied genetics 32 22903559
2010 Human intronic enhancers control distinct sub-domains of Gli3 expression during mouse CNS and limb development. BMC developmental biology 32 20426846
1998 Oligomeric interaction of the PapB transcriptional regulator with the upstream activating region of pili adhesin gene promoters in Escherichia coli. Molecular microbiology 32 9822817
2022 Detecting molecular interactions in live-cell single-molecule imaging with proximity-assisted photoactivation (PAPA). eLife 31 35976226
2018 Gli3 controls the onset of cortical neurogenesis by regulating the radial glial cell cycle through Cdk6 expression. Development (Cambridge, England) 31 30093555
2011 A three-part signal governs differential processing of Gli1 and Gli3 proteins by the proteasome. The Journal of biological chemistry 31 21921029
2010 Gli3 mediates cell survival and sensitivity to cyclopamine in pancreatic cancer. Cancer biology & therapy 30 20814245
2008 PAPA-1 Is a nuclear binding partner of IGFBP-2 and modulates its growth-promoting actions. Molecular endocrinology (Baltimore, Md.) 30 19095771
2001 Virulence genes and P fimbriae PapA subunit diversity in canine and feline uropathogenic Escherichia coli. Veterinary microbiology 30 11423198
2014 Signaling-State Formation Mechanism of a BLUF Protein PapB from the Purple Bacterium Rhodopseudomonas palustris Studied by Femtosecond Time-Resolved Absorption Spectroscopy. The journal of physical chemistry. B 29 25406769
2020 PAPA spectrum disorders. Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia 28 32618443
2018 Gli3 in fetal thymic epithelial cells promotes thymocyte positive selection and differentiation by repression of Shh. Development (Cambridge, England) 28 29361554
2017 Spop regulates Gli3 activity and Shh signaling in dorsoventral patterning of the mouse spinal cord. Developmental biology 28 28412462
2005 Genetic interaction of Gli3 and Alx4 during limb development. The International journal of developmental biology 28 15968591
2017 PKA-mediated Gli2 and Gli3 phosphorylation is inhibited by Hedgehog signaling in cilia and reduced in Talpid3 mutant. Developmental biology 27 28673820
2008 Identification of the gene transcription repressor domain of Gli3. FEBS letters 27 19084012
2009 Point mutations in GLI3 lead to misregulation of its subcellular localization. PloS one 25 19829694
1991 DNA sequences of three papA genes from uropathogenic Escherichia coli strains: evidence of structural and serological conservation. Infection and immunity 25 1682251
2021 GLI3 Is Stabilized by SPOP Mutations and Promotes Castration Resistance via Functional Cooperation with Androgen Receptor in Prostate Cancer. Molecular cancer research : MCR 24 34610962
2011 Abrogation of Gli3 expression suppresses the growth of colon cancer cells via activation of p53. Experimental cell research 23 22227409
2002 Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA syndrome) associated with hypogammaglobulinemia and elevated serum tumor necrosis factor-alpha levels. Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases 22 17041385
2020 GLI3 resides at the intersection of hedgehog and androgen action to promote male sex differentiation. PLoS genetics 21 32497091
2015 Differential requirements for Gli2 and Gli3 in the regional specification of the mouse hypothalamus. Frontiers in neuroanatomy 21 25859185
2010 Birth defects caused by mutations in human GLI3 and mouse Gli3 genes. Congenital anomalies 21 20201963
2007 A hypermorphic mouse Gli3 allele results in a polydactylous limb phenotype. Developmental dynamics : an official publication of the American Association of Anatomists 21 17266131
2004 Loss of Gli3 and Shh function disrupts olfactory axon trajectories. The Journal of comparative neurology 21 15065125
2019 Wnt5a is a transcriptional target of Gli3 and Trps1 at the onset of chondrocyte hypertrophy. Developmental biology 20 31550480
2006 Essential roles of Gli3 and sonic hedgehog in pattern formation and developmental anomalies caused by their dysfunction. Congenital anomalies 20 16922918
2020 A Unified Concept of Acne in the PAPA Spectrum Disorders. Dermatology (Basel, Switzerland) 19 32937626
2017 The transcription factor Gli3 promotes B cell development in fetal liver through repression of Shh. The Journal of experimental medicine 19 28533268
2019 Altered GLI3 and FGF8 signaling underlies acrocallosal syndrome phenotypes in Kif7 depleted mice. Human molecular genetics 18 30445565
2018 Imaging findings of sterile pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome: differential diagnosis and review of the literature. Pediatric radiology 18 30225645
2014 A novel GLI3 mutation affecting the zinc finger domain leads to preaxial-postaxial polydactyly-syndactyly complex. BMC medical genetics 18 25267529
2011 Shh and Gli3 regulate formation of the telencephalic-diencephalic junction and suppress an isthmus-like signaling source in the forebrain. Developmental biology 18 21925158
2006 HIP/PAP, a member of the reg family, is expressed in glucagon-producing enteropancreatic endocrine cells and tumors. Human pathology 18 16867870
2020 Downregulation of GLI3 Expression Mediates Chemotherapy Resistance in Acute Myeloid Leukemia. International journal of molecular sciences 17 32708452
2008 Mutational analysis of SHH and GLI3 in anorectal malformations. Birth defects research. Part A, Clinical and molecular teratology 17 18655123
2017 Direct Interactions Between Gli3, Wnt8b, and Fgfs Underlie Patterning of the Dorsal Telencephalon. Cerebral cortex (New York, N.Y. : 1991) 16 26656997
2016 Regulation of Expression of Uropathogenic Escherichia coli Nonfimbrial Adhesin TosA by PapB Homolog TosR in Conjunction with H-NS and Lrp. Infection and immunity 16 26755158
2015 GLI3 Links Environmental Arsenic Exposure and Human Fetal Growth. EBioMedicine 16 26288817
2014 Novel frame-shift mutations of GLI3 gene in non-syndromic postaxial polydactyly patients. Clinica chimica acta; international journal of clinical chemistry 16 24667698