Journal of Neuro-Oncology

, Volume 53, Issue 3, pp 307–318

A Mouse Model for Medulloblastoma and Basal Cell Nevus Syndrome

  • Ryan B. Corcoran
  • Matthew P. Scott


Medulloblastoma (MB), a tumor of the cerebellum, is the most frequent type of malignant childhood brain tumor. Multiple genes are causally involved in medulloblastoma including PATCHED1 (PTCH). The Patched1 (Ptc1) protein is a receptor for Sonic hedgehog (Shh), a secreted protein ligand. Shh is involved in many signaling processes that control cell fate and growth, among which is its emission from Purkinje cells in the developing cerebellum. Purkinje cell-derived Shh stimulates mitosis of the granule cell precursors that may be the cell type of origin in medulloblastoma. Ptc1 limits the effects of the Shh signal, so mutations in PTCH may lead to persistent granule cell precursors susceptible to further genetic or environmental events that cause medulloblastoma. Mice heterozygous for patched1 (ptc1) mutations, like heterozygous PTCH humans, have a high rate of medulloblastoma as well as other tumors. We discuss features of the mouse model and how it is contributing to understanding the process of brain tumorigenesis.

hedgehog patched gli medulloblastoma rhabdomyosarcoma 


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  1. 1.
    Cotran RS, Kumar V, Collins T: In: Robbins Pathologic Basis of Disease. W.B. Saunders Company, Philadelphia, PA, 1999Google Scholar
  2. 2.
    Goussia AC, Bruner JM, Kyritsis AP, Agnantis NJ, Fuller GN: Cytogenetic and molecular genetic abnormalities in primitive neuroectodermal tumors of the central nervous system. Anticancer Res 20: 65–73, 2000Google Scholar
  3. 3.
    Wetmore C, Eberhart DE, Curran T: The normal patched allele is expressed in medulloblastomas from mice with heterozygous germ-line mutation of patched. Cancer Res 60: 2239–2246, 2000Google Scholar
  4. 4.
    Gorlin RJ: Nevoid basal-cell carcinoma syndrome. Medicine (Baltimore) 66: 98–113, 1987Google Scholar
  5. 5.
    Beddis IR, Mott MG, Bullimore J: Case report: nasopharyngeal rhabdomyosarcoma and Gorlin's naevoid basal cell carcinoma syndrome. Med Pediatr Oncol 11: 178–179, 1983Google Scholar
  6. 6.
    Cowan R, Hoban P, Kelsey A, Birch JM, Gattamaneni R, Evans DG: The gene for the naevoid basal cell carcinoma syndrome acts as a tumour-suppressor gene in medulloblastoma. Br J Cancer 76: 141–145, 1997Google Scholar
  7. 7.
    Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, Quinn AG, Myers RM, Cox DR, Epstein EH Jr., Scott MP: Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272: 1668–1671, 1996Google Scholar
  8. 8.
    Mori T, Nagase H, Horii A, Miyoshi Y, Shimano T, Nakatsuru S, Aoki T, Arakawa H, Yanagisawa A, Ushio Y: Germline and somatic mutations of the APC gene in patients with Turcot syndrome and analysis of APC mutations in brain tumors. Genes Chromosomes Cancer 9: 168–172, 1994Google Scholar
  9. 9.
    Dong J, Gailani MR, Pomeroy SL, Reardon D, Bale AE: Identification of PATCHED mutations in medulloblastomas by direct sequencing. Hum Mutat 16: 89–90, 2000Google Scholar
  10. 10.
    Pietsch T, Waha A, Koch A, Kraus J, Albrecht S, Tonn J, Sorensen N, Berthold F, Henk B, Schmandt N, Wolf HK, von Deimling A, Wainwright B, Chenevix-Trench G, Wiestler OD, Wicking C: Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res 57: 2085–2088, 1997Google Scholar
  11. 11.
    Raffel C, Jenkins RB, Frederick L, Hebrink D, Alderete B, Fults DW, James CD: Sporadic medulloblastomas contain PTCH mutations. Cancer Res 57: 842–845, 1997Google Scholar
  12. 12.
    Vorechovsky I, Tingby O, Hartman M, Stromberg B, Nister M, Collins VP, Toftgard R: Somatic mutations in the human homologue of Drosophila patched in primitive neuroectodermal tumours. Oncogene 15: 361–366, 1997Google Scholar
  13. 13.
    Wolter M, Reifenberger J, Sommer C, Ruzicka T, Reifenberger G: Mutations in the human homologue of the Drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res 57: 2581–2585, 1997Google Scholar
  14. 14.
    Xie J, Johnson RL, Zhang X, Bare JW, Waldman FM, Cogen PH, Menon AG, Warren RS, Chen LC, Scott MP, Epstein EH Jr.: Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors. Cancer Res 57: 2369–2372, 1997Google Scholar
  15. 15.
    Lam CW, Xie J, To KF, Ng HK, Lee KC, Yuen NW, Lim PL, Chan LY, Tong SF, McCormick F: A frequent activated smoothened mutation in sporadic basal cell carcinomas. Oncogene 18: 833–836, 1999Google Scholar
  16. 16.
    Bridge JA, Liu J, Weibolt V, Baker KS, Perry D, Kruger R, Qualman S, Barr F, Sorensen P, Triche T, Suijkerbuijk R: Novel genomic imbalances in embryonal rhabdomyosarcoma revealed by comparative genomic hybridization and fluorescence in situ hybridization: an intergroup rhabdomyosarcoma study. Genes Chromosomes Cancer 27: 337–344, 2000Google Scholar
  17. 17.
    Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam CW, Hynes M, Goddard A, Rosenthal A, Epstein EH Jr, de Sauvage FJ: Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391: 90–92, 1998Google Scholar
  18. 18.
    Kinzler KW, Bigner SH, Bigner DD, Trent JM, Law ML, O'Brien SJ, Wong AJ, Vogelstein B: Identification of an amplified, highly expressed gene in a human glioma. Science 236: 70–73, 1987Google Scholar
  19. 19.
    Dahmane N, Lee J, Robins P, Heller P, Ruiz i Altaba A: Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. Nature 389: 876–881, 1997Google Scholar
  20. 20.
    Taipale J, Beachy PA: The Hedgehog and Wnt signalling pathways in cancer. Nature 411: 349–354, 2001Google Scholar
  21. 21.
    Goodrich LV, Scott MP: Hedgehog and patched in neural development and disease. Neuron 21: 1243–1257, 1998Google Scholar
  22. 22.
    Fuse N, Maiti T, Wang B, Proter JA, Hall TM, Leahy DJ, Beachy PA: Sonic hedgehog protein signals not as a hydrolytic enzyme but as an apparent ligand for patched. Proc Natl Acad Sci USA 96: 10992–10999, 1999Google Scholar
  23. 23.
    Gemmill RM, West JD, Boldog F, Tanaka N, Robinson LJ, Smith DI, Li F, Drabkin HA: The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8. Proc Natl Acad Sci USA 95: 9572–9577, 1998Google Scholar
  24. 24.
    Kenney AM, Rowitch DH: Sonic hedgehog promotes G(1) cyclin expression and sustained cell cycle progression in mammalian neuronal precursors. Mol Cell Biol 20: 9055–9067, 2000Google Scholar
  25. 25.
    Aszterbaum M, Epstein J, Oro A, Douglas V, LeBoit PE, Scott MP, Epstein EH Jr: Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice. Nat Med 5: 1285–1291, 1999Google Scholar
  26. 26.
    Goodrich LV, Milenkovic L, Higgins KM, Scott MP: Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277: 1109–1113, 1997Google Scholar
  27. 27.
    Hahn H, Wojnowski L, Zimmer AM, Hall J, Miler G, Zimmer A: Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome. Nat Med 4: 619–622, 1998Google Scholar
  28. 28.
    Zurawel RH, Allen C, Wechsler-Reya R, Scott MP, Raffel C: Evidence that haploinsufficiency of Ptch leads to medulloblastoma in mice. Genes Chromosomes Cancer 28: 77–81, 2000Google Scholar
  29. 29.
    Hahn H, Wojnowski L, Specht K, Kappler R, Calzada-Wack J, Potter D, Zimmer A, Muller U, Samson E, Quintanilla-Martinez L, Zimmer A: Patched target Igf2 is indispensable for the formation of medulloblastoma and rhabdomyosarcoma. J Biol Chem 275: 28341–28344, 2000Google Scholar
  30. 30.
    Dai P, Akimaru H, Tanaka Y, Maekawa T, Nakafuku M, Ishii S: Sonic hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. J Biol Chem 274: 8143–8152, 1999Google Scholar
  31. 31.
    Marigo V, Johnson RL, Vortkamp A, Tabin CJ: Sonic hedgehog differentially regulates expression of GLI and GLI3 during limb development. Dev Biol 180: 273–283, 1996Google Scholar
  32. 32.
    Sasaki H, Nishizaki Y, Hui C, Nakafuku M, Kondoh H: Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling. Development 126: 3915–3924, 1999Google Scholar
  33. 33.
    Wechsler-Reya RJ, Scott MP: Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron 22: 103–114, 1999Google Scholar
  34. 34.
    Wetmore C, Eberhart DE, Curran T: Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Res 61: 513–516, 2001Google Scholar
  35. 35.
    Dagher R, Helman L: Rhabdomyosarcoma: an overview. Oncologist 4: 34–44, 1999Google Scholar
  36. 36.
    Zhan S, Shapiro D, Zhan S, Zhang L, Hirschfeld S, Elassal J, Helman LJ: Concordant loss of imprinting of the human insulin-like growth factor II gene promoters in cancer. J Biol Chem 270: 27983–27986, 1995Google Scholar
  37. 37.
    Sun FL, Dean WL, Kelsey G, Allen ND, Reik W: Transactivation of Igf2 in a mouse model of Beckwith-Wiedemann syndrome. Nature 389: 809–815, 1997Google Scholar
  38. 38.
    DeChiara TM, Efstratiadis A, Robertson EJ: A growthdeficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature 345: 78–80, 1990Google Scholar
  39. 39.
    Albrecht S, Waha A, Koch A, Kraus JA, Goodyer CG, Pietsch T: Variable imprinting of H19 and IGF2 in fetal cerebellum and medulloblastoma. J Neuropathol Exp Neurol 55: 1270–1276, 1996Google Scholar
  40. 40.
    Miller DL, Weinstock MA: Nonmelanoma skin cancer in the United States: incidence. JAmAcad Dermatol 30: 774–778, 1994Google Scholar
  41. 41.
    Kimonis VE, Goldstein AM, Pastakia B, Yang ML, Kase R, DiGiovanna JJ, Bale AE, Bale SJ: Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet 69: 299–308, 1997Google Scholar
  42. 42.
    Fan H, Oro AE, Scott MP, Khavari PA: Induction of basal cell carcinoma features in transgenic human skin expressing Sonic hedgehog. Nat Med 3: 788–792, 1997Google Scholar
  43. 43.
    Nilsson M, Unden AB, Krause D, Malmqwist U, Raza K, Zaphiropoulos PG, Toftgard R: Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1. Proc Natl Acad Sci USA 97: 3438–3443, 2000Google Scholar
  44. 44.
    Oro AE, Higgins KM, Hu Z, Bonifas JM, Epstein EH Jr, Scott MP: Basal cell carcinomas in mice overexpressing sonic hedgehog. Science 276: 817–821, 1997Google Scholar
  45. 45.
    Mohler WA, Blau HM: Gene expression and cell fusion analyzed by lacZ complementation in mammalian cells. Proc Natl Acad Sci USA 93: 12423–12427, 1996Google Scholar
  46. 46.
    Kerr WG, Nolan GP, Herzenberg LA: In situ detection of transcriptionally active chromatin and genetic regulatory elements in individual viable mammalian cells. Immunol Suppl 2: 74–78, 1989Google Scholar
  47. 47.
    Lampson LA, Lampson MA, Dunne AD: Exploiting the lacZ reporter gene for quantitative analysis of disseminated tumor growth within the brain: use of the lacZ gene product as a tumor antigen, for evaluation of antigenic modulation, and to facilitate image analysis of tumor growth in situ. Cancer Res 53: 176–182, 1993Google Scholar
  48. 48.
    Zeltzer PM, Boyett JM, Finlay JL, Albright AL, Borke LB, Milstein JM, Allen JV, Stevens KR, Stanley P, Li H, Wisoff JH, Geyer JR, McGuire-Cullen P, Stehbens JA, Shurin SB, Packer RJ: Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921randomized phase III study. J Clin Oncol 17: 832–845, 1999Google Scholar
  49. 49.
    Johnson DL, McCabe MA, Nicholson HS, Joseph AL, Getson PR, Byrne J, Brasseux C, Packer RJ, Reaman G: Quality of long-term survival in young children with medulloblastoma. J Neurosurg 80: 1004–1010, 1994Google Scholar
  50. 50.
    Packer RJ: Childhood medulloblastoma: progress and future challenges. Brain Dev 21: 75–81, 1999Google Scholar
  51. 51.
    Reddy AT, Packer RJ: Medulloblastoma. Curr Opin Neurol 12: 681–685, 1999Google Scholar
  52. 52.
    Therond PP, Limbourg Bouchon B, Gallet A, Dussilol F, Pietri T, van den Heuvel M, Tricoire H: Differential requirements of the fused kinase for hedgehog signalling in the Drosophila embryo. Development 126: 4039–4051, 1999Google Scholar
  53. 53.
    Matise MP, Joyner AL: Gli genes in development and cancer. Oncogene 18: 7852–7859, 1999Google Scholar
  54. 54.
    Methot N, Basler K: An absolute requirement for Cubitus interruptus in Hedgehog signaling. Development 128: 733–742, 2001Google Scholar

Copyright information

© Kluwer Academic Publishers 2001

Authors and Affiliations

  • Ryan B. Corcoran
    • 1
  • Matthew P. Scott
    • 1
  1. 1.Departments of Developmental Biology and Genetics, Howard Hughes Medical Institute, Beckman Center B300Stanford University School of MedicineStanfordUSA

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