GLI3


GLI3

GLI-Kruppel family member GLI3 (Greig cephalopolysyndactyly syndrome), also known as GLI3, is a human gene.cite web | title = Entrez Gene: GLI3 GLI-Kruppel family member GLI3 (Greig cephalopolysyndactyly syndrome)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2737| accessdate = ]

This gene encodes a protein which 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.cite web | title = Entrez Gene: GLI3 GLI-Kruppel family member GLI3 (Greig cephalopolysyndactyly syndrome)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2737| accessdate = ]

Role in development

Gli3 is a known transcriptional repressor but may also have a positive transcriptional function.cite journal | author = Taipale J, Beachy PA | title = The Hedgehog and Wnt signalling pathways in cancer | journal = Nature | volume = 411 | issue = 6835 | pages = 349–54 | year = 2001 | pmid = 11357142 | doi = 10.1038/35077219 | issn = ] cite journal | author = Jacob J, Briscoe J | title = Gli proteins and the control of spinal-cord patterning | journal = EMBO Rep. | volume = 4 | issue = 8 | pages = 761–5 | year = 2003 | pmid = 12897799 | doi = 10.1038/sj.embor.embor896 | issn = ] Gli3 represses dHand and Germlin which are involved in developing digits.cite journal | author = 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 Dev. | volume = 16 | issue = 4 | pages = 421–6 | year = 2002 | pmid = 11850405 | doi = 10.1101/gad.219202 | issn = ] There is evidence that Shh-controlled processing (e.g cleavage) regulates transcriptional activity of Gli3 similarly to that of CI. Gli3 mutant mice have many abnormalities including CNS and lung defects and limb polydactyly.cite journal | author = 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 Anat (Basel) | volume = 150 | issue = 1 | pages = 38–44 | year = 1994 | pmid = 7976186 | doi = | issn = ] cite journal | author = 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 | year = 1998 | pmid = 9584130 | doi = | issn = | url = http://dev.biologists.org/cgi/content/abstract/125/12/2315 ] cite journal | author = 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 = Nat. Genet. | volume = 3 | issue = 3 | pages = 241–6 | year = 1993 | pmid = 8387379 | doi = 10.1038/ng0393-241 | issn = ] cite journal | author = 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 | year = 1992 | pmid = 1289066 | doi = | issn = | url = http://dev.biologists.org/cgi/content/abstract/116/3/799 ]

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.cite web | title = Entrez Gene: GLI3 GLI-Kruppel family member GLI3 (Greig cephalopolysyndactyly syndrome)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2737| accessdate = ]

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.cite journal | author = Böse J, Grotewold L, Rüther U | title = Pallister-Hall syndrome phenotype in mice mutant for Gli3 | journal = Hum. Mol. Genet. | volume = 11 | issue = 9 | pages = 1129–35 | year = 2002 | pmid = 11978771 | doi = 10.1093/hmg/11.9.1129 | issn = ]

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 BCC's. 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.cite journal | author = 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 | year = 1997 | pmid = 9349822 | doi = 10.1038/39918 | issn = ]

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 over expression of more that one Gli protein is not necessary for BCC formation.

References

External links

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