View source for GLI3

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''Zinc finger protein GLI3''' is a [[protein]] that in humans is encoded by the ''GLI3'' [[gene]].<ref name="pmid2118997">{{cite journal | vauthors = Ruppert JM, Vogelstein B, Arheden K, Kinzler KW | title = GLI3 encodes a 190-kilodalton protein with multiple regions of GLI similarity | journal = Molecular and Cellular Biology | volume = 10 | issue = 10 | pages = 5408–15 | date = October 1990 | pmid = 2118997 | pmc = 361243 | doi =  10.1128/mcb.10.10.5408}}</ref><ref name="entrez">{{cite web | title = Entrez Gene: GLI3 GLI-Kruppel family member GLI3 (Greig cephalopolysyndactyly syndrome)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2737}}</ref>

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 factor]]s and are mediators of [[Sonic hedgehog]] (Shh) [[hedgehog signaling pathway|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]].<ref name="entrez"/>

== Role in development ==
'''Gli3''' is a known [[transcription (genetics)|transcriptional]] [[repressor]] but may also have a positive transcriptional function.<ref name="pmid11357142">{{cite journal | vauthors = Taipale J, Beachy PA | title = The Hedgehog and Wnt signalling pathways in cancer | journal = Nature | volume = 411 | issue = 6835 | pages = 349–54 | date = May 2001 | pmid = 11357142 | doi = 10.1038/35077219 | bibcode = 2001Natur.411..349T | s2cid = 4414768 }}</ref><ref name=" Jacob_2003">{{cite journal | vauthors = Jacob J, Briscoe J | title = Gli proteins and the control of spinal-cord patterning | journal = EMBO Reports | volume = 4 | issue = 8 | pages = 761–5 | date = August 2003 | pmid = 12897799 | pmc = 1326336 | doi = 10.1038/sj.embor.embor896 }}</ref>  Gli3 represses [[HAND2|dHand]] and [[FIGLA|Gremlin]], which are involved in developing [[toe|digit]]s.<ref name="pmid11850405">{{cite journal | vauthors = te Welscher P, Fernandez-Teran M, Ros MA, Zeller R | title = Mutual genetic antagonism involving GLI3 and dHAND prepatterns the vertebrate limb bud mesenchyme prior to SHH signaling | journal = Genes & Development | volume = 16 | issue = 4 | pages = 421–6 | date = February 2002 | pmid = 11850405 | pmc = 155343 | doi = 10.1101/gad.219202 }}</ref>  There is evidence that [[Sonic hedgehog protein|Shh]]-controlled processing (e.g., cleavage) regulates transcriptional activity of Gli3 similarly to that of [[Cubitus interruptus|Ci]].<ref name=" Jacob_2003"/>  Gli3 mutant mice have many abnormalities including [[central nervous system|CNS]] and [[lung]] defects and limb [[polydactyly]].<ref>{{cite journal | vauthors = Rash BG, Grove EA | title = Patterning the dorsal telencephalon: a role for sonic hedgehog? | journal = The Journal of Neuroscience | volume = 27 | issue = 43 | pages = 11595–603 | date = October 2007 | pmid = 17959802 | doi = 10.1523/jneurosci.3204-07.2007 | pmc = 6673221 | doi-access = free }}</ref><ref name="pmid7976186">{{cite journal | vauthors = Franz T | title = Extra-toes (Xt) homozygous mutant mice demonstrate a role for the Gli-3 gene in the development of the forebrain | journal = Acta Anatomica | volume = 150 | issue = 1 | pages = 38–44 | year = 1994 | pmid = 7976186 | doi = 10.1159/000147600 }}</ref><ref name="pmid9584130">{{cite journal | vauthors = Grove EA, Tole S, Limon J, Yip L, Ragsdale CW | title = The hem of the embryonic cerebral cortex is defined by the expression of multiple Wnt genes and is compromised in Gli3-deficient mice | journal = Development | volume = 125 | issue = 12 | pages = 2315–25 | date = June 1998 | doi = 10.1242/dev.125.12.2315 | pmid = 9584130 }}</ref><ref name="pmid8387379">{{cite journal | vauthors = Hui CC, Joyner AL | title = A mouse model of greig cephalopolysyndactyly syndrome: the extra-toesJ mutation contains an intragenic deletion of the Gli3 gene | journal = Nature Genetics | volume = 3 | issue = 3 | pages = 241–6 | date = March 1993 | pmid = 8387379 | doi = 10.1038/ng0393-241 | s2cid = 345712 }}</ref><ref name="pmid1289066">{{cite journal | vauthors = Schimmang T, Lemaistre M, Vortkamp A, Rüther U | title = Expression of the zinc finger gene Gli3 is affected in the morphogenetic mouse mutant extra-toes (Xt) | journal = Development | volume = 116 | issue = 3 | pages = 799–804 | date = November 1992 | doi = 10.1242/dev.116.3.799 | pmid = 1289066 }}</ref>  In the developing mouse limb bud, Gli3 derepression predominantly regulates Shh target genes.<ref>{{cite journal | vauthors = Lewandowski JP, Du F, Zhang S, Powell MB, Falkenstein KN, Ji H, Vokes SA | date = Oct 2015 | title =  Spatiotemporal regulation of GLI target genes in the mammalian limb bud| journal = Dev. Biol. | volume = 406 | issue = 1| pages = 92–103 | doi = 10.1016/j.ydbio.2015.07.022 | pmid = 26238476 | pmc = 4587286}}</ref>

==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.<ref name="entrez"/> 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.<ref>{{cite journal | vauthors = Aiello KA, Ponnapalli SP, Alter O | title = Mathematically universal and biologically consistent astrocytoma genotype encodes for transformation and predicts survival phenotype | journal = APL Bioengineering | volume = 2 | issue = 3 | pages = 031909 | date = September 2018 | pmid = 30397684 | pmc = 6215493 | doi = 10.1063/1.5037882 }}</ref><ref>{{cite journal | vauthors = Aiello KA, Alter O | title = 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 | journal = PLOS ONE | volume = 11 | issue = 10 | pages = e0164546 | date = October 2016 | pmid = 27798635 | pmc = 5087864 | doi = 10.1371/journal.pone.0164546 | bibcode = 2016PLoSO..1164546A | doi-access = free }}</ref>

There is evidence that the [[autosome|autosomal]] [[dominant gene|dominant]] disorder [[Greig cephalopolysyndactyly syndrome]] (GCPS) that affects limb and craniofacial development in [[human]]s is caused by a translocations within the GLI3 gene.<ref name="pmid11978771">{{cite journal | vauthors = Böse J, Grotewold L, Rüther U | title = Pallister-Hall syndrome phenotype in mice mutant for Gli3 | journal = Human Molecular Genetics | volume = 11 | issue = 9 | pages = 1129–35 | date = May 2002 | pmid = 11978771 | doi = 10.1093/hmg/11.9.1129 | doi-access = free }}</ref>

==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 [[embryo]]nic 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.<ref name="pmid9349822">{{cite journal | vauthors = Dahmane N, Lee J, Robins P, Heller P, Ruiz i Altaba A | title = Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours | journal = Nature | volume = 389 | issue = 6653 | pages = 876–81 | date = October 1997 | pmid = 9349822 | doi = 10.1038/39918 | bibcode = 1997Natur.389..876D | s2cid = 4424572 }}</ref>

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 [[Protein-protein interaction|interact]] with [[CREB-binding protein|CREBBP]]<ref name="pmid10075717">{{cite journal | vauthors = Dai P, Akimaru H, Tanaka Y, Maekawa T, Nakafuku M, Ishii S | title = Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3 | journal = The Journal of Biological Chemistry | volume = 274 | issue = 12 | pages = 8143–52 | date = March 1999 | pmid = 10075717 | doi = 10.1074/jbc.274.12.8143 | doi-access = free }}</ref> [[SUFU]],<ref name="pmid20360384">{{cite journal | vauthors = Humke EW, Dorn KV, Milenkovic L, Scott MP, Rohatgi R | title = The output of Hedgehog signaling is controlled by the dynamic association between Suppressor of Fused and the Gli proteins | journal = Genes & Development | volume = 24 | issue = 7 | pages = 670–82 | date = April 2010 | pmid = 20360384 | pmc = 2849124 | doi = 10.1101/gad.1902910 }}</ref> [[ZIC1]],<ref name="pmid11238441">{{cite journal | vauthors = Koyabu Y, Nakata K, Mizugishi K, Aruga J, Mikoshiba K | title = Physical and functional interactions between Zic and Gli proteins | journal = The Journal of Biological Chemistry | volume = 276 | issue = 10 | pages = 6889–92 | date = March 2001 | pmid = 11238441 | doi = 10.1074/jbc.C000773200 | doi-access = free }}</ref> and [[ZIC2]].<ref name=pmid11238441/>

== References ==
{{Reflist}}

== External links ==
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=phs  GeneReviews/NCBI/NIH/UW entry on Pallister-Hall Syndrome]
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=gcps  GeneReviews/NCBI/NIH/UW entry on Greig Cephalopolysyndactyly Syndrome]
* {{MeshName|GLI3+protein,+human}}

{{NLM content}}
{{Transcription factors|g2}}
{{Hedgehog signaling pathway}}

{{DEFAULTSORT:Gli3}}
[[Category:Transcription factors]]