Gli3 is a known transcriptionalrepressor but may also have a positive transcriptional function. Gli3 represses dHand and Gremlin, which are involved in developing digits. 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. In the developing mouse limb bud, Gli3 derepression predominately regulates Shh target genes.
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. 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.
The independent overexpressionGli1 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.
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.
^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. PMID7976186.
^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. PMID9584130.
^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. PMID8387379.
^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. PMID1289066.
^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. PMID11978771.
^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. PMID9349822.
^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. PMID10075717.
^ abKoyabu 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. PMID11238441.