During embryonic development all cells of the central nervous system originate from primitive neuroepithelial cells, a population of rapidly-proliferating cells lining the central neural tube. Medulloblastoma is a malignant brain tumor afflicting young children which is presently incurable and usually fatal. It is believed that medulloblastoma are caused by mutational events affecting primitive neuroepithelial cells and preventing their differentiation into post-mitotic neurons. I have found that the human medulloblastoma cell line, TE 671, contains an activated N-ras oncogene which transforms NIH 3T3 cells in DNA-mediated gene transfer experiments. The objective of this research proposal is to study the mechanism of oncogenic activation in TE 671 cells and in human medulloblastoma tumors. This objective will be approached along three lines of investigation. First, oligonucleotide hybridization assays enhanced through in vitro amplification of N-ras coding sequences will be used to identify the point mutation in the N-ras gene responsible for its activation in TE 671 cells. Second, in order to identify recessive oncogenes in medulloblastoma patients, pairs of somatic and tumor DNA's will be examined by Southern transfer analysis using a panel of highly polymorphic DNA markers for human chromosomes. A tumor-specific chromosome deletion discovered in this way would point to a recessive gene which may play a role in normal neuronal differentiation. Third, amplified genes which may represent novel oncogenes will be sought in TE 671 cells and in medulloblastoma tumors by gel denaturation-renaturation techniques. Any insights which this study provides into the molecular events governing oncogenesis in medulloblastomas will have important implications for not only neuro-oncology, but also neural development.
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