The epidermal growth factor receptor (EGFR) gene is amplified or mutated in 30-50% of human glioblastoma multiforme. These mutations are usually associated with deletions of the INK4a-ARF locus, which encodes 2 gene products (p16INK4a and p19ARF) involved in cell cycle arrest and apoptosis. We have investigated the role of EGFR mutation in gliomagenesis using avian retroviral vectors to transfer a mutant EGFR gene to glial precursors and astrocytes in transgenic mice. These mice express tv-a, a gene encoding the retrovirus receptor TVA, which is under the control of brain cell type-specific promoters. We demonstrate that expression of a constitutively active, mutant form of EGFR in cells in the glial lineage can induce lesions with many similarities to human gliomas, including increased cell density, vascular proliferation, and immunohistochemical staining for glial fibrillary acidic protein (GFAP) and nestin. We also demonstrate that primary astrocytes cultured from transgenic mice expressing tv-a from the GFAP promoter are efficiently infected in culture, and such genetically modified cell cultures can be tumorigenic in nude mice. The combinations of genetic lesions (eg, mutated EGFR, INK4a-/-) leading to tumor formation in these 2 mouse systems are similar to those found in human gliomas. These genetically defined animal models for gliomas will allow for the testing of therapies that are targeted specifically at the gene products involved in the pathogenesis of gliomas.