NCI CLINICAL INVESTIGATOR AWARD PROGRAM

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During embryogenesis the neurons and glia of the central nervous system arise by differentiation from rapidly proliferating primitive neuroepithelial cells. Very little is known about the molecular mechanisms of neuronal and glial differentiation and proliferation, but the study of retroviral oncogenes has recently provided a means of investigating these mechanisms. pp60c-src, the normal cellular homolog of the transforming protein pp60v-src of Rous sarcoma virus, is expressed at elevated levels in embryonic neurons at the onset of differentiation. Recently, I established that pp60c-src was the product of differentiating neurons in the cerebullum of the developing chick embryo. However, its precise functional role there is still unknown. The expression of the normal cellular src gene in the developing chick cerebellum will be studied in order to help decipher the role of this gene in neuronal and possibly glial differentiation. First, cell cultures enriched for neurons and glia will be prepared from embryonic chick cerebellum and the expression of pp60c-src in these cell cultures will be studied by immunocytochemistry. This study will identify a subcellular localization for pp60c-src in the young neuron and will also determine the level of pp60c-src expression in glial cells compared to normal cells. A role for pp60c-src in controlling the proliferation or differentiation of glial cells is suggested by the ability of the very similar but mutant protein, pp60v-src, to induce gliomas in rats infected with Rous sarcoma virus. To investigate the action of the pp60v-src in gliomas, a panel of mouse monoclonal antibodies will be prepared against Rous sarcoma virus (RSV)-induced gliomas in rats. These monoclonal antibodies will be used to probe the expression of glioma-specific antigens in the developing rat brain. Expression of tumor-specific antigens during normal neural development may suggest that neoplastic transformation of glial cells by RSV involves expression of genes that are important during fetal development.