The effect of oncogenes on the growth and differentiation of oligodendrocyte type 2 astrocyte progenitor cells.

Oncogenes represent altered versions of cellular genes instrumental for control of cell proliferation and differentiation. Several oncogenes have been implicated in glial cell transformation and immortalization in culture (myc, src, mos, ras, and SV40 large T antigen). The purpose of this study is to further our understanding of glial cell neoplasia by investigating the effect of oncogenes on the growth and differentiation of central nervous system glial progenitor cells from the oligodendrocyte type 2 astrocyte (O-2A) lineage. This progenitor cell differentiates into an oligodendrocyte or a type-2 astrocyte according to environmental cues. Drug-selectable retroviral vectors were used to introduce oncogenes either alone or in combination into primary cultures of rat O-2A cells. Established O-2A progenitor cell lines were only obtained after infection with c-myc or SV40 large T antigen, suggesting that among the oncogenes tested only these were capable of immortalizing O-2A progenitor cells. The O-2A/c-myc and O-2A/temperature-sensitive SV40 large T antigen cell lines retained the capacity to differentiate into oligodendrocytes and type-2 astrocytes, thereby providing an opportunity to study the effects of oncogene cooperation on the phenotype of O-2A lineage cells. Superinfection of these cells lines with retroviruses encoding ras or src led to abnormalities of differentiation whose nature and severity depended on the combination of cooperating oncogenes and/or the levels of expression obtained. This study demonstrates that oncogene-modified glial cell lines provide an amenable and unique model system to study differentiation in the central nervous system and the genetic changes involved in the development of glioma.