THE EFFECT OF ONCOGENES ON THE GROWTH AND DIFFERENTIATION OF OLIGODENDROCYTE TYPE-2 ASTROCYTE PROGENITOR CELLS

Oncogenes represent altered versions of cellular genes instrumental fo r 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 purpos e of this study is to further our understanding of glial cell neoplasi a by investigating the effect of oncogenes on the growth and different iation of central nervous system glial progenitor cells from the oligo dendrocyte type 2 astrocyte (O-2A) lineage. This progenitor cell diffe rentiates into an oligodendrocyte or a type-2 astrocyte according to e nvironmental cues. Drug-selectable retroviral vectors were used to int roduce oncogenes either alone or in combination into primary cultures of rat O-2A cells. Established O-2A progenitor cell lines were only ob tained after infection with c-myc or SV40 large T antigen, suggesting that among the oncogenes tested only these were capable of immortalizi ng O-2A progenitor cells. The O-2A/c-myc and O-2A/temperature-sensitiv e SV40 targe T antigen cell lines retained the capacity to differentia te into oligodendrocytes and type-2 astrocytes, thereby providing an o pportunity to study the effects of oncogene cooperation on the phenoty pe of O-2A lineage cells. Superinfection of these cells lines with ret roviruses encoding ras or src led to abnormalities of differentiation whose nature and severity depended on the combination of cooperating o ncogenes and/or the levels of expression obtained. This study demonstr ates that oncogene-modified glial cell lines provide an amenable and u nique model system to study differentiation in the central nervous sys tem and the genetic changes involved in the development of glioma.