Tumour Induction in Fetal Brain Transplants Exposed to the Viral Oncogenes Polyoma Middle T and V-src

Using a neural transplantation model, we have studied the effect of polyoma virus middle T antigen and of the viral src oncogene on the developing rat brain. For this purpose, single-cell suspensions of fetal rat brain were prepared on day 14 of gestation (E14), infected with a replication-defective retroviral vector which carries the middle T oncogene driven by an internal thymidine kinase promoter, and stereotaxically injected into the caudoputamen of adult host rats. With mock-infected donor cells, the transplants developed into an organotypically differentiated population of neurons, astrocytes, oligodendrocytes and other central nervous system cell types and expressed marker proteins of mature neuroectodermal cells, including neuron-specific enolase, synaptophysin, neurofilament protein, glial fibrillary acidic protein and S-100 protein. A high percentage of rats carrying transplants infected with the middle T-encoding vector died within two to six weeks from massive haemorrhage into the transplant. Upon microscopic examination, gross abnormalities of the microvasculature were seen, with formation of large blood-filled spaces lined by a thin layer of proliferating endothelial cells. This effect of middle T was apparently cell type-specific, since the differentiation of neuroectodermal cells within the graft proceeded in a regular fashion. In order to assess further the cell-specificity of the oncogene, analogous experiments were carried out with a retroviral construct in which the middle T cDNA had been replaced by the viral src gene (v-src). Transplants infected with the v-src vector developed astrocytomas, but no vascular abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)