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Null mutation of DNA strand break-binding molecule poly(ADP-ribose) polymerase causes medulloblastomas in p53(-/-)
Wei-Min Tong1, Hiroko Ohgaki, Huatao Huang
1International Agency for Research on Cancer (IARC), Lyon, France.
Abstract:
Medulloblastoma is an invasive embryonal tumor of the cerebellum with predominant neuronal differentiation. Although several genes have been implicated in medulloblasoma formation, such as Patched (Ptc1) and the adenomatous polyposis coli gene (Apc), the majority of these tumors cannot be explained by mutations in these genes. The cellular origin as well as the genetic and molecular changes involved in the genesis and progression of human medulloblastomas remain largely unknown. Here we show that disruption of poly(ADP-ribose) polymerase (PARP-1) causes a high incidence (49%) of aggressive brain tumors in p53 null mice, with typical features of human cerebellar medulloblastomas. At as early as 8 weeks of age, lesions started on the outer surface of the cerebellum from remnant granule cell precursors of the developmental external germinal layer. Progression of these tumors is associated with the re-activation of the neuronal specific transcription factor Math1, dysregulation of Shh/Ptc1 signaling pathway, and chromosomal aberrations, including triradial and quadriradial chromosomes. The present study indicates that the loss of function of DNA double-strand break-sensing and repair molecules is an etiological factor in the evolution of the cerebellar medulloblastomas. These PARP-1/p53 double null mice represent a novel model for the pathogenesis of human medulloblastomas.
Insights
Disrupting poly(ADP-ribose) polymerase (PARP-1) in mice lacking p53 triggers aggressive brain tumors, offering a new model for medulloblastoma research. This finding highlights the role of DNA repair in tumor development.
Area of Science:
- Neuro-oncology
- Genetics
- Molecular Biology
Background:
- Medulloblastoma is a common pediatric brain tumor with poorly understood origins.
- While genes like Ptc1 and Apc are implicated, many medulloblastomas lack mutations in known genes.
- The cellular origin and molecular drivers of medulloblastoma remain largely unknown.
Purpose of the Study:
- To investigate the role of poly(ADP-ribose) polymerase 1 (PARP-1) in medulloblastoma development.
- To establish a novel mouse model for studying medulloblastoma pathogenesis.
Main Methods:
- Generation of p53 null mice with disrupted poly(ADP-ribose) polymerase (PARP-1).
- Analysis of tumor incidence, histology, and molecular alterations in the generated mouse model.
- Examination of gene expression (Math1), signaling pathways (Shh/Ptc1), and chromosomal aberrations.
Main Results:
- PARP-1 disruption in p53 null mice led to a 49% incidence of aggressive cerebellar tumors resembling human medulloblastomas.
- Tumor development originated from cerebellar external germinal layer precursors.
- Tumor progression involved re-activation of Math1, Shh/Ptc1 pathway dysregulation, and chromosomal abnormalities.
Conclusions:
- Loss of function in DNA double-strand break repair molecules, such as PARP-1, is a significant etiological factor in cerebellar medulloblastoma.
- PARP-1/p53 double null mice provide a valuable new model for studying medulloblastoma pathogenesis and progression.