JAX Notes April 01, 2003

Medulloblastoma mouse models

Medulloblastomas are the most common pediatric tumor of the posterior fossa (1). They generally develop in children between the ages of 3 to 9 and make up about 20% of all childhood brain tumors. Medulloblastomas are more common in males than females. Most arise from the primitive neuroectoderm and grow into the fourth ventricle, causing anterior displacement with associated hydrocephalus.

Though there has been significant progress using mouse models to study medulloblastomas, the molecular and genetic basis of the disease is not clearly understood. Mouse strains having targeted mutations of the tumor suppressor gene (Trp53), the Hedgehog pathway gene Patched 1 (Ptch), and the DNA repair enzyme ADP-ribosyltransferase (NAD+; poly (ADP-ribose) polymerase) 1 (Adprt1), also known as PARP, are considered valuable models for studying medulloblastomas.

The Jackson Laboratory maintains strains that are defective in Trp53, Ptch, and Adprt1 (See Table 1). Notably, the B6;129-Ptchtm1Mps strain developed by Dr. Matthew Scott is a model for Gorlin's syndrome and is perhaps one of the most widely used medulloblastoma models.

Table 1. The Jackson Laboratory maintains several strains that serve as models for studying medulloblastomas.

Strain Name Stock Number

B6.129S2-Trp53tm1Tyj

002101

B6;129-Ptchtm1Mps

003081

129S-Adprt1tm1Zqw

002779

In the early 2000s, mouse models developed by Wetmore and colleagues, and by Tong and colleagues have shown to be potentially very useful for medulloblastoma research (1,2). By using a combination of strains that are defective in Trp53, Ptch, and Adprt1, they have generated two mouse models that display a more aggressive medulloblastoma phenotype.

More than 95% of mice that are homozygous null for Trp53 and heterozygous for Ptch develop tumors in the posterior fossa between 10 and 12 weeks of age (1). In contrast, Trp53 homozygous null mice, which exhibit some of the features of Li-Fraumeni syndrome, develop spontaneous medulloblastomas with an incidence of approximately 5% (3). Ptch heterozygous mice develop medulloblastoma-like tumors with an incidence of approximately 14% by 6 months of age, while Ptch homozygous null mice die during embryogenesis(1).

Slightly less than 50% of mice homozygous null for both Trp53 and Adprt1 develop brain tumors starting at 8 weeks of age, with males developing more than twice as many tumors as females, a phenomenon also seen in humans(2).

Histological analysis shows that 30% of brain tumors are localized in the cerebellum, and large tumors often compress the cerebellar hemispheres and invade the fourth ventricle (2). Although mice homozygous null for both Trp53 and Adprt1 do not develop tumors at the same rate as mice that are homozygous null for Trp53 and heterozygous for Ptch, they represent a novel model for human medulloblastoma.

References

  1. Wetmore C, Eberhart DE, Curran T. Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Res 2001; 61:513-516.
  2. Tong WM, Ohgaki H, Huang H, Granier C, Kleihues P, Wang ZQ. Null mutation of DNA strand break-binding molecule poly(ADP-ribose) polymerase causes medulloblastomas in p53(-/-) Mice. Am J Pathol 2003; 162:343-352.
  3. Eberhart CG. Medulloblastoma in mice lacking p53 and PARP: all roads lead to Gli. Am J Pathol 2003;162:7-10.
  4. Goodrich LV, Milenkovic L, Higgins KM, Scott MP. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 1997; 277:1109-1113.