GLI3

GLI family zinc finger 3
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 4BLD​
Identifiers
Symbols	GLI3 ; ACLS; GCPS; GLI3-190; GLI3FL; PAP-A; PAPA; PAPA1; PAPB; PHS; PPDIV
External IDs	OMIM: 165240 MGI: 95729 HomoloGene: 139 GeneCards: GLI3 Gene
Gene ontology Molecular function • RNA polymerase II core promoter proximal region sequence-specific DNA binding • RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription • chromatin binding • sequence-specific DNA binding transcription factor activity • protein binding • beta-catenin binding • histone acetyltransferase binding • histone deacetylase binding • metal ion binding Cellular component • nucleus • nucleoplasm • cytoplasm • cytosol • cilium • axoneme • mediator complex • nuclear speck • transcriptional repressor complex • primary cilium • ciliary tip • ciliary base Biological process • negative regulation of transcription from RNA polymerase II promoter • metanephros development • branching involved in ureteric bud morphogenesis • in utero embryonic development • positive regulation of neuroblast proliferation • transcription from RNA polymerase II promoter • smoothened signaling pathway • axon guidance • hindgut morphogenesis • heart development • negative regulation of cell proliferation • anterior/posterior pattern specification • proximal/distal pattern formation • protein processing • optic nerve morphogenesis • hippocampus development • smoothened signaling pathway involved in ventral spinal cord interneuron specification • smoothened signaling pathway involved in spinal cord motor neuron cell fate specification • forebrain dorsal/ventral pattern formation • cerebral cortex radial glia guided migration • forebrain radial glial cell differentiation • lateral ganglionic eminence cell proliferation • melanocyte differentiation • lung development • positive regulation of chondrocyte differentiation • T cell differentiation in thymus • limb morphogenesis • wound healing • positive regulation of protein import into nucleus • odontogenesis of dentin-containing tooth • embryonic digit morphogenesis • negative regulation of apoptotic process • nose morphogenesis • tongue development • response to estrogen • negative thymic T cell selection • negative regulation of neuron differentiation • positive regulation of osteoblast differentiation • negative regulation of smoothened signaling pathway • negative regulation of transcription, DNA-templated • positive regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • positive regulation of alpha-beta T cell differentiation • negative regulation of alpha-beta T cell differentiation • embryonic digestive tract morphogenesis • embryonic digestive tract development • developmental growth • camera-type eye morphogenesis • embryonic skeletal system morphogenesis • oligodendrocyte differentiation • palate development • frontal suture morphogenesis • lambdoid suture morphogenesis • sagittal suture morphogenesis • mammary gland specification • smoothened signaling pathway involved in dorsal/ventral neural tube patterning • artery development • anterior semicircular canal development • lateral semicircular canal development • cell differentiation involved in kidney development • thymocyte apoptotic process • negative regulation of canonical Wnt signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2737	14634
Ensembl	ENSG00000106571	ENSMUSG00000021318
UniProt	P10071	Q61602
RefSeq (mRNA)	NM_000168	NM_008130
RefSeq (protein)	NP_000159	NP_032156
Location (UCSC)	Chr 7: 41.96 – 42.24 Mb	Chr 13: 15.46 – 15.73 Mb
PubMed search

Zinc finger protein GLI3 is a protein that in humans is encoded by the GLI3 gene.^[1][2]

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.^[2]

Role in development

Gli3 is a known transcriptional repressor but may also have a positive transcriptional function.^[3][4] Gli3 represses dHand and Gremlin, which are involved in developing digits.^[5] There is evidence that Shh-controlled processing (e.g., cleavage) regulates transcriptional activity of Gli3 similarly to that of CI.^[4] Gli3 mutant mice have many abnormalities including CNS and lung defects and limb polydactyly.^{[6][7][8][9][10]}

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.^[2]

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.^[11]

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.^[12]

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.

Interactions

GLI3 has been shown to interact with CREBBP^[13] SUFU,^[14] ZIC1,^[15] and ZIC2.^[15]

References

1. Ruppert JM, Vogelstein B, Arheden K, Kinzler KW (Oct 1990). "GLI3 encodes a 190-kilodalton protein with multiple regions of GLI similarity". Mol Cell Biol 10 (10): 5408–15. PMC 361243. PMID 2118997.
2. "Entrez Gene: GLI3 GLI-Kruppel family member GLI3 (Greig cephalopolysyndactyly syndrome)".
3. Taipale J, Beachy PA (2001). "The Hedgehog and Wnt signalling pathways in cancer". Nature 411 (6835): 349–54. doi:10.1038/35077219. PMID 11357142.
4. Jacob J, Briscoe J (2003). "Gli proteins and the control of spinal-cord patterning". EMBO Rep. 4 (8): 761–5. doi:10.1038/sj.embor.embor896. PMC 1326336. PMID 12897799.
5. te Welscher P, Fernandez-Teran M, Ros MA, Zeller R (2002). "Mutual genetic antagonism involving GLI3 and dHAND prepatterns the vertebrate limb bud mesenchyme prior to SHH signaling". Genes Dev. 16 (4): 421–6. doi:10.1101/gad.219202. PMC 155343. PMID 11850405.
6. Rash, BG; Grove, EA (24 October 2007). "Patterning the dorsal telencephalon: a role for sonic hedgehog?". The Journal of neuroscience : the official journal of the Society for Neuroscience 27 (43): 11595–603. doi:10.1523/jneurosci.3204-07.2007. PMID 17959802.
7. Franz T (1994). "Extra-toes (Xt) homozygous mutant mice demonstrate a role for the Gli-3 gene in the development of the forebrain". Acta Anat (Basel) 150 (1): 38–44. doi:10.1159/000147600. PMID 7976186.
8. Grove EA, Tole S, Limon J, Yip L, Ragsdale CW (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.
9. Hui CC, Joyner AL (1993). "A mouse model of greig cephalopolysyndactyly syndrome: the extra-toesJ mutation contains an intragenic deletion of the Gli3 gene". Nat. Genet. 3 (3): 241–6. doi:10.1038/ng0393-241. PMID 8387379.
10. Schimmang T, Lemaistre M, Vortkamp A, Rüther U (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.
11. Böse J, Grotewold L, Rüther U (2002). "Pallister-Hall syndrome phenotype in mice mutant for Gli3". Hum. Mol. Genet. 11 (9): 1129–35. doi:10.1093/hmg/11.9.1129. PMID 11978771.
12. Dahmane N, Lee J, Robins P, Heller P, Ruiz i Altaba A (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.
13. 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". J. Biol. Chem. 274 (12): 8143–52. doi:10.1074/jbc.274.12.8143. PMID 10075717.
14. 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 Dev. 24 (7): 670–82. doi:10.1101/gad.1902910. PMC 2849124. PMID 20360384.
15. Koyabu Y, Nakata K, Mizugishi K, Aruga J, Mikoshiba K (March 2001). "Physical and functional interactions between Zic and Gli proteins". J. Biol. Chem. 276 (10): 6889–92. doi:10.1074/jbc.C000773200. PMID 11238441.

External links

• GeneReviews/NCBI/NIH/UW entry on Pallister-Hall Syndrome
• GeneReviews/NCBI/NIH/UW entry on Greig Cephalopolysyndactyly Syndrome
• GLI3 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.