Available structures
PDBOrtholog search: PDBe RCSB
Aliases GLI3, ACLS, GCPS, GLI3-190, GLI3FL, PAP-A, PAPA, PAPA1, PAPB, PHS, PPDIV, GLI family zinc finger 3
External IDs OMIM: 165240 MGI: 95729 HomoloGene: 139 GeneCards: GLI3
Genetically Related Diseases
age related macular degeneration, allergic rhinitis[1]
RNA expression pattern
More reference expression data
Species Human Mouse









RefSeq (mRNA)



RefSeq (protein)



Location (UCSC) Chr 7: 41.96 – 42.24 Mb Chr 13: 15.46 – 15.73 Mb
PubMed search [2] [3]
View/Edit HumanView/Edit Mouse

Zinc finger protein GLI3 is a protein that in humans is encoded by the GLI3 gene.[4][5]

This gene encodes a protein that belongs to the C2H2-type zinc finger proteins subclass of the Gli family. They are characterized as DNA-binding transcription factors and are mediators of Sonic hedgehog (Shh) signaling. The protein encoded by this gene localizes in the cytoplasm and activates patched Drosophila homolog (PTCH1) gene expression. It is also thought to play a role during embryogenesis.[5]

Role in development

Gli3 is a known transcriptional repressor but may also have a positive transcriptional function.[6][7] Gli3 represses dHand and Gremlin, which are involved in developing digits.[8] There is evidence that Shh-controlled processing (e.g., cleavage) regulates transcriptional activity of Gli3 similarly to that of Ci.[7] Gli3 mutant mice have many abnormalities including CNS and lung defects and limb polydactyly.[9][10][11][12][13]

Disease association

Mutations in this gene have been associated with several diseases, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, and postaxial polydactyly types A1 and B.[5] DNA copy-number alterations that contribute to increased conversion of the oncogenes Gli1–3 into transcriptional activators by the Hedgehog signaling pathway are included in a genome-wide pattern, which was found to be correlated with an astrocytoma patient’s outcome.[14]

There is evidence that the autosomal dominant disorder Greig cephalopolysyndactyly syndrome (GCPS) that affects limb and craniofacial development in humans is caused by a translocations within the GLI3 gene.[15]

Interactions with Gli1 and Gli2

The independent overexpression Gli1 and Gli2 in mice models to lead to formation of basal cell carcinoma (BCC). Gli1 knockout is shown to lead to similar embryonic malformations as Gli1 overexpressions but not the formation of BCCs. Overexpression of Gli3 in transgenic mice and frogs does not lead to the development of BCC-like tumors and is not thought to play a role in tumor BCC formation.[16]

Gli1 and Gli2 overexpression leads to BCC formation in mouse models and a one step model for tumour formation has been suggested in both cases. This also indicates that Gli1 and/or Gli2 overexpression is vital in BCC formation. Co-overexpression of Gli1 with Gli2 and Gli2 with Gli3 leads to transgenic mice malformations and death, respectively, but not the formation of BCC. This suggests that overexpression of more than one Gli protein is not necessary for BCC formation.


GLI3 has been shown to interact with CREBBP[17] SUFU,[18] ZIC1,[19] and ZIC2.[19]


  1. "Diseases that are genetically associated with GLI3 view/edit references on wikidata".
  2. "Human PubMed Reference:".
  3. "Mouse PubMed Reference:".
  4. Ruppert JM, Vogelstein B, Arheden K, Kinzler KW (October 1990). "GLI3 encodes a 190-kilodalton protein with multiple regions of GLI similarity". Molecular and Cellular Biology. 10 (10): 5408–15. PMC 361243Freely accessible. PMID 2118997.
  5. 1 2 3 "Entrez Gene: GLI3 GLI-Kruppel family member GLI3 (Greig cephalopolysyndactyly syndrome)".
  6. Taipale J, Beachy PA (May 2001). "The Hedgehog and Wnt signalling pathways in cancer". Nature. 411 (6835): 349–54. doi:10.1038/35077219. PMID 11357142.
  7. 1 2 Jacob J, Briscoe J (August 2003). "Gli proteins and the control of spinal-cord patterning". EMBO Reports. 4 (8): 761–5. doi:10.1038/sj.embor.embor896. PMC 1326336Freely accessible. PMID 12897799.
  8. te Welscher P, Fernandez-Teran M, Ros MA, Zeller R (February 2002). "Mutual genetic antagonism involving GLI3 and dHAND prepatterns the vertebrate limb bud mesenchyme prior to SHH signaling". Genes & Development. 16 (4): 421–6. doi:10.1101/gad.219202. PMC 155343Freely accessible. PMID 11850405.
  9. Rash BG, Grove EA (October 2007). "Patterning the dorsal telencephalon: a role for sonic hedgehog?". The Journal of Neuroscience. 27 (43): 11595–603. doi:10.1523/jneurosci.3204-07.2007. PMID 17959802.
  10. Franz T (1994). "Extra-toes (Xt) homozygous mutant mice demonstrate a role for the Gli-3 gene in the development of the forebrain". Acta Anatomica. 150 (1): 38–44. doi:10.1159/000147600. PMID 7976186.
  11. Grove EA, Tole S, Limon J, Yip L, Ragsdale CW (June 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. 125 (12): 2315–25. PMID 9584130.
  12. Hui CC, Joyner AL (March 1993). "A mouse model of greig cephalopolysyndactyly syndrome: the extra-toesJ mutation contains an intragenic deletion of the Gli3 gene". Nature Genetics. 3 (3): 241–6. doi:10.1038/ng0393-241. PMID 8387379.
  13. Schimmang T, Lemaistre M, Vortkamp A, Rüther U (November 1992). "Expression of the zinc finger gene Gli3 is affected in the morphogenetic mouse mutant extra-toes (Xt)". Development. 116 (3): 799–804. PMID 1289066.
  14. K. A. Aiello; O. Alter (October 2016). "Platform-Independent Genome-Wide Pattern of DNA Copy-Number Alterations Predicting Astrocytoma Survival and Response to Treatment Revealed by the GSVD Formulated as a Comparative Spectral Decomposition". PLOS ONE. 11 (10): e0164546. doi:10.1371/journal.pone.0164546.
  15. Böse J, Grotewold L, Rüther U (May 2002). "Pallister-Hall syndrome phenotype in mice mutant for Gli3". Human Molecular Genetics. 11 (9): 1129–35. doi:10.1093/hmg/11.9.1129. PMID 11978771.
  16. Dahmane N, Lee J, Robins P, Heller P, Ruiz i Altaba A (October 1997). "Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours". Nature. 389 (6653): 876–81. doi:10.1038/39918. PMID 9349822.
  17. Dai P, Akimaru H, Tanaka Y, Maekawa T, Nakafuku M, Ishii S (March 1999). "Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3". The Journal of Biological Chemistry. 274 (12): 8143–52. doi:10.1074/jbc.274.12.8143. PMID 10075717.
  18. Humke EW, Dorn KV, Milenkovic L, Scott MP, Rohatgi R (April 2010). "The output of Hedgehog signaling is controlled by the dynamic association between Suppressor of Fused and the Gli proteins". Genes & Development. 24 (7): 670–82. doi:10.1101/gad.1902910. PMC 2849124Freely accessible. PMID 20360384.
  19. 1 2 Koyabu Y, Nakata K, Mizugishi K, Aruga J, Mikoshiba K (March 2001). "Physical and functional interactions between Zic and Gli proteins". The Journal of Biological Chemistry. 276 (10): 6889–92. doi:10.1074/jbc.C000773200. PMID 11238441.

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