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Gene Review

Gli2  -  GLI-Kruppel family member GLI2

Mus musculus

Synonyms: AW546128, Tax helper protein, Thp, Zinc finger protein GLI2
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Disease relevance of Gli2

  • Gli2 mutants were found to have abnormal development of maxillary incisors, probably resulting from a mild holoprosencephaly, whereas Gli3 mutants had no major tooth abnormalities [1].
  • Interestingly, Gli2 levels were elevated in medulloblastoma cells but not in normal granule neuron precursors during cerebellar development in mice lacking Gli1 [2].
  • When grown as a subcapsular graft, the Gli2(-/-) UGS exhibited prostatic differentiation but also displayed areas of focal epithelial hyperplasia [3].
  • A reduction of 50% in the gene dosage of Gli3 in a Gli2-/- background resulted in oesophageal atresia with tracheo-oesophageal fistula and a severe lung phenotype [4].
  • We report here that mutant mice lacking Gli2 function exhibit foregut defects, including stenosis of the oesophagus and trachea, as well as hypoplasia and lobulation defects of the lung [4].

High impact information on Gli2


Biological context of Gli2

  • Although the Gli1, Gli2, and Gli3 zinc finger proteins are known to be effectors of Hh signaling in vertebrates, the mechanisms regulating activity of these transcription factors remain poorly understood [3] [4] [8].
  • These results demonstrate that Gli2 and Gli3 share common regulatory mechanisms and modulate Hedgehog target gene expression directly and independently while also regulating Gli1 expression, which in specific contexts, coordinately contributes to target gene activation [9].
  • We have found that the floor plate throughout the midbrain, hindbrain and spinal cord does not form in Gli2 homozygotes [10].
  • To further define their roles in regulating myogenesis, the function of wild type and dominant-negative forms of Gli2 and Meox1 were examined in the context of differentiating P19 stem cells [11].
  • The Ptc1(-/-) phenotype is rescued, with restoration of dorsal cell types, by the lack of Gli2, but only in the caudal neural tube [12].

Anatomical context of Gli2

  • In cultured fibroblasts, Gli1 was more potent than Gli2 at inducing cell transformation [2].
  • The family consists of Gli(1), Gli2, and Gli3, all of which are expressed in the developing mouse limb bud [13].
  • Interestingly, Gli2 and Gli3 (C.-c. Hui and A. L. Joyner (1993). Nature Genet. 3, 241-246) mutant mice exhibit different subsets of skeletal defects indicating that they implement specific functions in the development of the neural crest, somite and lateral plate mesoderm derivatives [14].
  • Gli2 mutants fail to develop a floor plate yet still develop motor neurons, which occupy the ventral midline of the neural tube [15].
  • In cultured cells, truncation of the activation domain in the C-terminal half results in a protein with repressor activity, while removal of the repression domain at the N terminus converts Gli2 into a strong activator [16].

Associations of Gli2 with chemical compounds

  • The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3 [17].
  • These results underscore the qualitative difference in oncogenicity of GLI1 and Gli2 when overexpressed in skin, and reveal a previously unanticipated role for the Gli2 NH(2) terminus in defining tumor phenotype [18].

Regulatory relationships of Gli2

  • By contrast, Gli2 is expressed uniformly in all cells in the developing cerebellum except Purkinje cells and Gli3 is broadly expressed along the anteroposterior axis [19].
  • Luciferase assay showed that the 3.6-kb Fgf15 enhancer/promoter was activated by Gli2 [20].

Other interactions of Gli2

  • In addition, specific components in the Hedgehog pathway are either ectopically activated (Ptc, Ptc-2, Gli1) or repressed (Gli2) [21].
  • The Shh signalling pathway in tooth development: defects in Gli2 and Gli3 mutants [1].
  • Together, our data demonstrate both positive and negative regulatory functions for Gli2 and Gli3 in the control of Myf5 activation in the epaxial muscle progenitor cells and in dorsoventral and mediolateral patterning of the somite [22].
  • Taken together, these results support the existence of a regulatory loop between Gli2, Meox1, and Pax3 that is essential for specification of mesodermal cells into the muscle lineage [11].
  • The zinc finger transcription factor Gli2 mediates bone morphogenetic protein 2 expression in osteoblasts in response to hedgehog signaling [23].

Analytical, diagnostic and therapeutic context of Gli2


  1. The Shh signalling pathway in tooth development: defects in Gli2 and Gli3 mutants. Hardcastle, Z., Mo, R., Hui, C.C., Sharpe, P.T. Development (1998) [Pubmed]
  2. Gli1 is important for medulloblastoma formation in Ptc1+/- mice. Kimura, H., Stephen, D., Joyner, A., Curran, T. Oncogene (2005) [Pubmed]
  3. Functional compensation in Hedgehog signaling during mouse prostate development. Doles, J., Cook, C., Shi, X., Valosky, J., Lipinski, R., Bushman, W. Dev. Biol. (2006) [Pubmed]
  4. Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus. Motoyama, J., Liu, J., Mo, R., Ding, Q., Post, M., Hui, C.C. Nat. Genet. (1998) [Pubmed]
  5. Notch1 functions as a tumor suppressor in mouse skin. Nicolas, M., Wolfer, A., Raj, K., Kummer, J.A., Mill, P., van Noort, M., Hui, C.C., Clevers, H., Dotto, G.P., Radtke, F. Nat. Genet. (2003) [Pubmed]
  6. Basal cell carcinomas in mice overexpressing Gli2 in skin. Grachtchouk, M., Mo, R., Yu, S., Zhang, X., Sasaki, H., Hui, C.C., Dlugosz, A.A. Nat. Genet. (2000) [Pubmed]
  7. Sonic hedgehog-dependent activation of Gli2 is essential for embryonic hair follicle development. Mill, P., Mo, R., Fu, H., Grachtchouk, M., Kim, P.C., Dlugosz, A.A., Hui, C.C. Genes Dev. (2003) [Pubmed]
  8. Mouse suppressor of fused is a negative regulator of sonic hedgehog signaling and alters the subcellular distribution of Gli1. Ding, Q., Fukami, S., Meng, X., Nishizaki, Y., Zhang, X., Sasaki, H., Dlugosz, A., Nakafuku, M., Hui, C. Curr. Biol. (1999) [Pubmed]
  9. Unique and complimentary activities of the Gli transcription factors in Hedgehog signaling. Lipinski, R.J., Gipp, J.J., Zhang, J., Doles, J.D., Bushman, W. Exp. Cell Res. (2006) [Pubmed]
  10. Gli2 is required for induction of floor plate and adjacent cells, but not most ventral neurons in the mouse central nervous system. Matise, M.P., Epstein, D.J., Park, H.L., Platt, K.A., Joyner, A.L. Development (1998) [Pubmed]
  11. Disruption of Meox or Gli activity ablates skeletal myogenesis in P19 cells. Petropoulos, H., Gianakopoulos, P.J., Ridgeway, A.G., Skerjanc, I.S. J. Biol. Chem. (2004) [Pubmed]
  12. Differential requirement for Gli2 and Gli3 in ventral neural cell fate specification. Motoyama, J., Milenkovic, L., Iwama, M., Shikata, Y., Scott, M.P., Hui, C.C. Dev. Biol. (2003) [Pubmed]
  13. Expression profile of Gli family members and Shh in normal and mutant mouse limb development. Büscher, D., Rüther, U. Dev. Dyn. (1998) [Pubmed]
  14. Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development. Mo, R., Freer, A.M., Zinyk, D.L., Crackower, M.A., Michaud, J., Heng, H.H., Chik, K.W., Shi, X.M., Tsui, L.C., Cheng, S.H., Joyner, A.L., Hui, C. Development (1997) [Pubmed]
  15. Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice. Ding, Q., Motoyama, J., Gasca, S., Mo, R., Sasaki, H., Rossant, J., Hui, C.C. Development (1998) [Pubmed]
  16. Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling. Sasaki, H., Nishizaki, Y., Hui, C., Nakafuku, M., Kondoh, H. Development (1999) [Pubmed]
  17. Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Pan, Y., Bai, C.B., Joyner, A.L., Wang, B. Mol. Cell. Biol. (2006) [Pubmed]
  18. Dissecting the oncogenic potential of Gli2: deletion of an NH(2)-terminal fragment alters skin tumor phenotype. Sheng, H., Goich, S., Wang, A., Grachtchouk, M., Lowe, L., Mo, R., Lin, K., de Sauvage, F.J., Sasaki, H., Hui, C.C., Dlugosz, A.A. Cancer Res. (2002) [Pubmed]
  19. Spatial pattern of sonic hedgehog signaling through Gli genes during cerebellum development. Corrales, J.D., Rocco, G.L., Blaess, S., Guo, Q., Joyner, A.L. Development (2004) [Pubmed]
  20. Expression of the mouse Fgf15 gene is directly initiated by Sonic hedgehog signaling in the diencephalon and midbrain. Saitsu, H., Komada, M., Suzuki, M., Nakayama, R., Motoyama, J., Shiota, K., Ishibashi, M. Dev. Dyn. (2005) [Pubmed]
  21. Evidence that preaxial polydactyly in the Doublefoot mutant is due to ectopic Indian Hedgehog signaling. Yang, Y., Guillot, P., Boyd, Y., Lyon, M.F., McMahon, A.P. Development (1998) [Pubmed]
  22. Gli2 and Gli3 have redundant and context-dependent function in skeletal muscle formation. McDermott, A., Gustafsson, M., Elsam, T., Hui, C.C., Emerson, C.P., Borycki, A.G. Development (2005) [Pubmed]
  23. The zinc finger transcription factor Gli2 mediates bone morphogenetic protein 2 expression in osteoblasts in response to hedgehog signaling. Zhao, M., Qiao, M., Harris, S.E., Chen, D., Oyajobi, B.O., Mundy, G.R. Mol. Cell. Biol. (2006) [Pubmed]
  24. Gli3 null mice display glandular overgrowth of the developing stomach. Kim, J.H., Huang, Z., Mo, R. Dev. Dyn. (2005) [Pubmed]
  25. Gli2 is required for normal Shh signaling and oligodendrocyte development in the spinal cord. Qi, Y., Tan, M., Hui, C.C., Qiu, M. Mol. Cell. Neurosci. (2003) [Pubmed]
  26. Defective sonic hedgehog signaling in esophageal atresia with tracheoesophageal fistula. Spilde, T.L., Bhatia, A.M., Mehta, S., Ostlie, D.J., Hembree, M.J., Preuett, B.L., Prasadan, K., Li, Z., Snyder, C.L., Gittes, G.K. Surgery (2003) [Pubmed]
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