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Gene Review

Gli3  -  GLI-Kruppel family member GLI3

Mus musculus

Synonyms: AI854843, AU023367, Bph, GLI3 form of 190 kDa, GLI3 full length protein, ...
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Disease relevance of Gli3


High impact information on Gli3

  • Finally, by fate mapping Shh-responding cells in Gli2 and Gli3 mutant limbs, we demonstrate that a specific level of positive Hh signaling is not required to specify digit identities [6].
  • Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus [1].
  • The Xt heterozygotes show craniofacial defects and a polydactyly phenotype similar to GCPS [7].
  • Gli3 (the gene implicated in human Greig cephalopolysyndactyly syndrome) is proposed to negatively regulate Shh by restricting its expression and influence to the posterior mesoderm [8].
  • However, whereas these cell identities are restored in Gli3/Smo compound mutants, correct stratification of the rescued ventral cell types is lost [9].

Chemical compound and disease context of Gli3


Biological context of Gli3

  • Gli3 is required for Emx gene expression during dorsal telencephalon development [12].
  • However, its importance for lung development is shown by the finding that Gli3XtJ embryos, homozygous for a mutation involving a deletion of the Gli3 gene, have a stereotypic pattern of abnormalities in lung morphogenesis [13].
  • In Shh(-/-) or cyclopamine-treated wild-type (WT) lung, we found that Gli3R level is elevated, and this upregulation appears to contribute to defects in proliferation and differentiation observed in the Shh(-/-) mesenchyme, where Gli3 is normally expressed [14].
  • Sonic hedgehog signaling regulates Gli3 processing, mesenchymal proliferation, and differentiation during mouse lung organogenesis [14].
  • 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 [15].

Anatomical context of Gli3

  • Here, we report on forebrain development in the extra toes (Xt(J)) mouse mutant which carries a null mutation of the Gli3 gene [12].
  • However, expression of Shh, which is negatively regulated by Gli3 in the spinal cord, is not affected in the Xt(J)/Xt(J) forebrain [12].
  • 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 [16].
  • Gli2 and Gli3 have redundant and context-dependent function in skeletal muscle formation [16].
  • 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 [17].

Associations of Gli3 with chemical compounds


Regulatory relationships of Gli3


Other interactions of Gli3

  • Interplays of Gli2 and Gli3 and their requirement in mediating Shh-dependent sclerotome induction [28].
  • A similar regulatory mechanism involving the N-terminal region was also found for Gli3, but not for Gli1 [29].
  • Expression of Gli3 and Hand2 in the mutant limb indicates that the limb prepattern is abnormal [30].
  • The present study shows that establishment and positioning of the polarising region is regulated both by restriction of Shh through Gli3 and its positive feedback regulation through formin [31].
  • In Hx mice we found a down-regulation of Gli3 in the anterior region of the limb bud [32].

Analytical, diagnostic and therapeutic context of Gli3


  1. 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]
  2. 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]
  3. The transcription factor Gli3 regulates differentiation of fetal CD4- CD8- double-negative thymocytes. Hager-Theodorides, A.L., Dessens, J.T., Outram, S.V., Crompton, T. Blood (2005) [Pubmed]
  4. Dysregulation of hedgehog signalling predisposes to synovial chondromatosis. Hopyan, S., Nadesan, P., Yu, C., Wunder, J., Alman, B.A. J. Pathol. (2005) [Pubmed]
  5. The mouse mutant Polydactyly Nagoya (Pdn) defines a novel allele of the zinc finger gene Gli3. Schimmang, T., Oda, S.I., Rüther, U. Mamm. Genome (1994) [Pubmed]
  6. Dynamic changes in the response of cells to positive hedgehog signaling during mouse limb patterning. Ahn, S., Joyner, A.L. Cell (2004) [Pubmed]
  7. A mouse model of greig cephalopolysyndactyly syndrome: the extra-toesJ mutation contains an intragenic deletion of the Gli3 gene. Hui, C.C., Joyner, A.L. Nat. Genet. (1993) [Pubmed]
  8. Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Litingtung, Y., Dahn, R.D., Li, Y., Fallon, J.F., Chiang, C. Nature (2002) [Pubmed]
  9. A direct requirement for Hedgehog signaling for normal specification of all ventral progenitor domains in the presumptive mammalian spinal cord. Wijgerde, M., McMahon, J.A., Rule, M., McMahon, A.P. Genes Dev. (2002) [Pubmed]
  10. Genetic susceptibility in the neural tube defects induced by ochratoxin A in the genetic arhinencephaly mouse, Pdn/Pdn. Ohta, K., Maekawa, M., Katagiri, R., Ueta, E., Naruse, I. Congenital anomalies. (2006) [Pubmed]
  11. Effects of all-trans-retinoic acid on limb development in the genetic polydactyly mouse. Tamagawa, M., Morita, J., Naruse, I. The Journal of toxicological sciences. (1995) [Pubmed]
  12. Gli3 is required for Emx gene expression during dorsal telencephalon development. Theil, T., Alvarez-Bolado, G., Walter, A., Rüther, U. Development (1999) [Pubmed]
  13. Evidence for the involvement of the Gli gene family in embryonic mouse lung development. Grindley, J.C., Bellusci, S., Perkins, D., Hogan, B.L. Dev. Biol. (1997) [Pubmed]
  14. Sonic hedgehog signaling regulates Gli3 processing, mesenchymal proliferation, and differentiation during mouse lung organogenesis. Li, Y., Zhang, H., Choi, S.C., Litingtung, Y., Chiang, C. Dev. Biol. (2004) [Pubmed]
  15. 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]
  16. 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]
  17. 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]
  18. Vertebrate homologs of Drosophila suppressor of fused interact with the gli family of transcriptional regulators. Pearse, R.V., Collier, L.S., Scott, M.P., Tabin, C.J. Dev. Biol. (1999) [Pubmed]
  19. Loss of Gli3 enhances the viability of embryonic telencephalic cells in vitro. Zaki, P.A., Martynoga, B., Delafield-Butt, J.T., Fotaki, V., Yu, T., Price, D.J. Eur. J. Neurosci. (2005) [Pubmed]
  20. Neuro-glial neurotrophic interaction in the S-100 beta retarded mutant mouse (Polydactyly Nagoya). III. Transplantation study. Ueda, S., Aikawa, M., Kawata, M., Naruse, I., Whitaker-Azmitia, P.M., Azmitia, E.C. Brain Res. (1996) [Pubmed]
  21. Neuro-glial neurotrophic interaction in the S-100 beta retarded mutant mouse (Polydactyly Nagoya). I. Immunocytochemical and neurochemical studies. Ueda, S., Gu, X.F., Whitaker-Azmitia, P.M., Naruse, I., Azmitia, E.C. Brain Res. (1994) [Pubmed]
  22. The arrest of luteinizing hormone-releasing hormone neuronal migration in the genetic arhinencephalic mouse embryo (Pdn/Pdn). Naruse, I., Fukui, Y., Keino, H., Taniguchi, M. Brain Res. Dev. Brain Res. (1994) [Pubmed]
  23. Mouse Rab23 regulates hedgehog signaling from smoothened to Gli proteins. Eggenschwiler, J.T., Bulgakov, O.V., Qin, J., Li, T., Anderson, K.V. Dev. Biol. (2006) [Pubmed]
  24. Ski is involved in transcriptional regulation by the repressor and full-length forms of Gli3. Dai, P., Shinagawa, T., Nomura, T., Harada, J., Kaul, S.C., Wadhwa, R., Khan, M.M., Akimaru, H., Sasaki, H., Colmenares, C., Ishii, S. Genes Dev. (2002) [Pubmed]
  25. Ihh controls cartilage development by antagonizing Gli3, but requires additional effectors to regulate osteoblast and vascular development. Hilton, M.J., Tu, X., Cook, J., Hu, H., Long, F. Development (2005) [Pubmed]
  26. Zic1 regulates the patterning of vertebral arches in cooperation with Gli3. Aruga, J., Mizugishi, K., Koseki, H., Imai, K., Balling, R., Noda, T., Mikoshiba, K. Mech. Dev. (1999) [Pubmed]
  27. Extra-toes (Xt) homozygous mutant mice demonstrate a role for the Gli-3 gene in the development of the forebrain. Franz, T. Acta anatomica. (1994) [Pubmed]
  28. Interplays of Gli2 and Gli3 and their requirement in mediating Shh-dependent sclerotome induction. Buttitta, L., Mo, R., Hui, C.C., Fan, C.M. Development (2003) [Pubmed]
  29. 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]
  30. Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Liu, A., Wang, B., Niswander, L.A. Development (2005) [Pubmed]
  31. Gli3 (Xt) and formin (ld) participate in the positioning of the polarising region and control of posterior limb-bud identity. Zúñiga, A., Zeller, R. Development (1999) [Pubmed]
  32. Expression profile of Gli family members and Shh in normal and mutant mouse limb development. Büscher, D., Rüther, U. Dev. Dyn. (1998) [Pubmed]
  33. Gli3 mutation rescues the generation, but not the differentiation, of oligodendrocytes in Shh mutants. Tan, M., Hu, X., Qi, Y., Park, J., Cai, J., Qiu, M. Brain Res. (2006) [Pubmed]
  34. Sonic hedgehog pathway inhibition alters epididymal function as assessed by the development of sperm motility. Turner, T.T., Bang, H.J., Attipoe, S.A., Johnston, D.S., Tomsig, J.L. J. Androl. (2006) [Pubmed]
  35. All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3. Bai, C.B., Stephen, D., Joyner, A.L. Dev. Cell (2004) [Pubmed]
  36. Sonic hedgehog expression in Gli3 depressed mouse embryo, Pdn/Pdn. Ueta, E., Maekawa, M., Morimoto, I., Nanba, E., Naruse, I. Congenital anomalies. (2004) [Pubmed]
  37. Cloning and sequence analysis of the murine Gli3 cDNA. Thien, H., Büscher, D., Rüther, U. Biochim. Biophys. Acta (1996) [Pubmed]
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