Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Gli1 is important for medulloblastoma formation in Ptc1+/− mice

Abstract

Germline mutations in the human homolog of the patched1 (PTCH1) are associated with basal cell nevus carcinoma syndrome (BCNS or Gorlin syndrome), which is characterized by developmental anomalies, radiation hypersensitivity and a predisposition to medulloblastomas and skin tumors. Patched1 (Ptc1) functions as a receptor for Sonic hedgehog (Shh) in a wide range of biological processes. Binding of Shh to Ptc1 results in activation of Smoothened (Smo), which in turn stimulates expression of downstream target genes including Ptc1 and Gli1. Gli1 is a member of a family of DNA-binding zinc-finger proteins, including Gli2 and Gli3, that function in transcription control. Here, we report that inactivation of both Gli1 alleles in Ptc1+/− mice significantly reduces spontaneous medulloblastoma formation. Therefore, Gli1 is not only a marker of pathway activation but also plays a functional role in medulloblastoma formation. Interestingly, Gli2 levels were elevated in medulloblastoma cells but not in normal granule neuron precursors during cerebellar development in mice lacking Gli1. In cultured fibroblasts, Gli1 was more potent than Gli2 at inducing cell transformation. These results demonstrate that Gli1 plays a central role in medulloblastoma formation in Ptc1+/− mice and that Gli2 may also contribute to oncogenesis.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Bai CB, Auerbach W, Lee JS, Stephen D and Joyner AL . (2002). Development, 129, 4753–4761.

  • Bai CB and Joyner AL . (2001). Development, 128, 5161–5172.

  • Berman DM, Karhadkar SS, Hallahan AR, Pritchard JI, Eberhart CG, Watkins DN, Chen JK, Cooper MK, Taipale J, Olson JM and Beachy PA . (2002). Science, 297, 1559–1561.

  • Calzada-Wack J, Kappler R, Schnitzbauer U, Richter T, Nathrath M, Rosemann M, Wagner SN, Hein R and Hahn H . (2002). Carcinogenesis, 23, 727–733.

  • Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, Westphal H and Beachy PA . (1996). Nature, 383, 407–413.

  • Ciemerych MA, Kenney AM, Sicinska E, Kalaszczynska I, Bronson RT, Rowitch DH, Gardner H and Sicinski P . (2002). Genes Dev., 16, 3277–3289.

  • Corrales JD, Rocco GL, Blaess S, Guo Q and Joyner AL . (2004). Development, 131, 5581–5590.

  • Dahmane N and Ruiz-i-Altaba A . (1999). Development, 126, 3089–3100.

  • Dai P, Akimaru H, Tanaka Y, Maekawa T, Nakafuku M and Ishii S . (1999). J. Biol. Chem., 274, 8143–8152.

  • Dong J, Gailani MR, Pomeroy SL, Reardon D and Bale AE . (2000). Hum. Mutat., 16, 89–90.

  • Frank-Kamenetsky M, Zhang XM, Bottega S, Guicherit O, Wichterle H, Dudek H, Bumcrot D, Wang FY, Jones S, Shulok J, Rubin LL and Porter JA . (2002). J. Biol., 1, 10.

  • Goodrich LV, Milenkovic L, Higgins KM and Scott MP . (1997). Science, 277, 1109–1113.

  • Goodrich LV and Scott MP . (1998). Neuron., 21, 1243–1257.

  • Gorlin RJ . (1987). Medicine (Baltimore), 66, 98–113.

  • Grachtchouk M, Mo R, Yu S, Zhang X, Sasaki H, Hui CC and Dlugosz AA . (2000). Nat. Genet., 24, 216–217.

  • Grachtchouk V, Grachtchouk M, Lowe L, Johnson T, Wei L, Wang A, de Sauvage F and Dlugosz AA . (2003). EMBO J., 22, 2741–2751.

  • Hui CC and Joyner AL . (1993). Nat. Genet., 3, 241–246.

  • Ingham PW and McMahon AP . (2001). Genes. Dev., 15, 3059–3087.

  • Kenney AM, Cole MD and Rowitch DH . (2003). Development, 130, 15–28.

  • Kenney AM, Widlund HR and Rowitch DH . (2004). Development, 131, 217–228.

  • Kimura H and Shiota K . (2003). J. Biol. Chem., 278, 4806–4812.

  • Klein RS, Rubin JB, Gibson HD, DeHaan EN, Alvarez-Hernandez X, Segal RA and Luster AD . (2001). Development, 128, 1971–1981.

  • Knoepfler PS, Cheng PF and Eisenman RN . (2002). Genes. Dev., 16, 2699–2712.

  • Koyabu Y, Nakata K, Mizugishi K, Aruga J and Mikoshiba K . (2001). J. Biol. Chem., 276, 6889–6892.

  • Lee Y, Miller HL, Jensen P, Hernan R, Connelly M, Wetmore C, Zindy F, Roussel MF, Curran T, Gilbertson RJ and McKinnon PJ . (2003). Cancer Res., 63, 5428–5437.

  • Lewis PM, Gritli-Linde A, Smeyne R, Kottmann A and McMahon AP . (2004). Dev. Biol., 270, 393–410.

  • Miao GG and Curran T . (1994). Mol. Cell Biol., 14, 4295–4310.

  • Mo R, Freer AM, Zinyk DL, Crackower MA, Michaud J, Heng HH, Chik KW, Shi XM, Tsui LC, Cheng SH, Joyner AL and Hui C . (1997). Development, 124, 113–123.

  • Nilsson M, Unden AB, Krause D, Malmqwist U, Raza K, Zaphiropoulos PG and Toftgard R . (2000). Proc. Natl. Acad. Sci. USA, 97, 3438–3443.

  • Oliver TG, Grasfeder LL, Carroll AL, Kaiser C, Gillingham CL, Lin SM, Wickramasinghe R, Scott MP and Wechsler-Reya RJ . (2003). Proc. Natl. Acad. Sci. USA, 100, 7331–7336.

  • Oro AE and Higgins K . (2003). Dev. Biol., 255, 238–248.

  • Oro AE, Higgins KM, Hu Z, Bonifas JM, Epstein Jr EH and Scott MP . (1997). Science, 276, 817–821.

  • Park HL, Bai C, Platt KA, Matise MP, Beeghly A, Hui CC, Nakashima M and Joyner AL . (2000). Development, 127, 1593–1605.

  • Pazzaglia S, Mancuso M, Atkinson MJ, Tanori M, Rebessi S, Majo VD, Covelli V, Hahn H and Saran A . (2002). Oncogene, 21, 7580–7584.

  • Pomeroy SL, Tamayo P, Gaasenbeek M, Sturla LM, Angelo M, McLaughlin ME, Kim JY, Goumnerova LC, Black PM, Lau C, Allen JC, Zagzag D, Olson JM, Curran T, Wetmore C, Biegel JA, Poggio T, Mukherjee S, Rifkin R, Califano A, Stolovitzky G, Louis DN, Mesirov JP, Lander ES and Golub TR . (2002). Nature, 415, 436–442.

  • Raffel C, Jenkins RB, Frederick L, Hebrink D, Alderete B, Fults DW and James CD . (1997). Cancer Res., 57, 842–845.

  • Reifenberger J, Wolter M, Weber RG, Megahed M, Ruzicka T, Lichter P and Reifenberger G . (1998). Cancer Res., 58, 1798–1803.

  • Romer JT, Kimura H, Magdaleno S, Sasai K, Fuller C, Baines H, Connelly M, Stewart CF, Gould S, Rubin LL and Curran T . (2004). Cancer Cell., 6, 229–240.

  • Ruppert JM, Vogelstein B and Kinzler KW . (1991). Mol. Cell. Biol., 11, 1724–1728.

  • Sasaki H, Nishizaki Y, Hui C, Nakafuku M and Kondoh H . (1999). Development, 126, 3915–3924.

  • Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X, Agatep R, Chiappa S, Gao L, Lowrance A, Hao A, Goldstein AM, Stavrou T, Scherer SW, Dura WT, Wainwright B, Squire JA, Rutka JT and Hogg D . (2002). Nat. Genet., 31, 306–310.

  • Tong WM, Ohgaki H, Huang H, Granier C, Kleihues P and Wang ZQ . (2003). Am. J. Pathol., 162, 343–352.

  • Vorechovsky I, Tingby O, Hartman M, Stromberg B, Nister M, Collins VP and Toftgard R . (1997). Oncogene, 15, 361–366.

  • Wallace VA . (1999). Curr. Biol., 9, 445–448.

  • Wechsler-Reya RJ and Scott MP . (1999). Neuron, 22, 103–114.

  • Weiner HL, Bakst R, Hurlbert MS, Ruggiero J, Ahn E, Lee WS, Stephen D, Zagzag D, Joyner AL and Turnbull DH . (2002). Cancer Res., 62, 6385–6389.

  • Wetmore C, Eberhart DE and Curran T . (2000). Cancer Res., 60, 2239–2246.

  • Wetmore C, Eberhart DE and Curran T . (2001). Cancer Res., 61, 513–516.

  • Wolter M, Reifenberger J, Sommer C, Ruzicka T and Reifenberger G . (1997). Cancer Res., 57, 2581–2585.

  • Xie J, Johnson RL, Zhang X, Bare JW, Waldman FM, Cogen PH, Menon AG, Warren RS, Chen LC, Scott MP and Epstein Jr EH . (1997). Cancer Res., 57, 2369–2372.

  • Zhao Q, Kho A, Kenney AM, Yuk Di DI, Kohane I and Rowitch DH . (2002). Proc. Natl. Acad. Sci. USA, 99, 5704–5709.

  • Zurawel RH, Allen C, Chiappa S, Cato W, Biegel J, Cogen P, de Sauvage F and Raffel C . (2000a). Genes Chromosomes Cancer, 27, 44–51.

  • Zurawel RH, Allen C, Wechsler-Reya R, Scott MP and Raffel C . (2000b). Genes Chromosomes Cancer, 28, 77–81.

Download references

Acknowledgements

We thank Drs Hiroshi Sasaki for Gli1, Gli2 clones and Gli-luc reporter plasmids, Shunsuke Ishii for F-Gli3 plasmid, Suzanne Baker for the VP16 clone, Allen Bale for anti-Ptc1 antiserum, and Peter McKinnon for N-myc and c-myc clones. We also thank Curran lab members for critical reading of the manuscript and helpful comments. We are grateful to Ms Michele Connelly for technical assistance. We thank Mehmet Kocak, Dana Wallace and Dr James Boyett for statistical analyses. This work was supported by a grant CA096832 from the National Institutes of Health and the American Lebanese Syrian Associated Charities (ALSAC) (TC). AJ is an investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tom Curran.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kimura, H., Stephen, D., Joyner, A. et al. Gli1 is important for medulloblastoma formation in Ptc1+/− mice. Oncogene 24, 4026–4036 (2005). https://doi.org/10.1038/sj.onc.1208567

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208567

Keywords

This article is cited by

Search

Quick links