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Transformation of Astrocytes in Transgenic Mice Expressing SV40 T Antigen under the Transcriptional Control of the Glial Fibrillary Acidic Protein Promoter¹

Neuroscience Laboratory, Department of Neurosurgery and University Department of Surgery, Royal Melbourne Hospital, 3050 Melbourne, Australia [R. A. D., J. M. O., A. H. K.]; Neuropathology Research Laboratory, Department of Anatomical Pathology, Royal Melbourne Hospital, Melbourne, Australia [M. F. G.]; Department of Anatomy, The University of Melbourne, Melbourne, Australia [S-S. T.]; Department of Surgery (Royal Melbourne Hospital), The University of Melbourne, Parkville, 3052 Victoria, Australia [B. A.]; and Department of Molecular Neurobiology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan [K. M.]

There are many animal models of glioma, but few that represent the biology of low-grade tumors and allow the study of the genetic mechanisms of glial oncogenesis. We report the in vivo transformation of astrocytic cells in transgenic mice by the SV40 T antigen under the control of the 5'-flanking sequence of the murine glial fibrillary acidic protein (GFAP) gene. High levels of T antigen expression were detectable in a tissue distribution that mirrored the normal expression of GFAP. This was associated with a consistent phenotype in the founder mice. Diffuse proliferation occurred in cells of the periventricular subependymal zone with diffuse invasion into the brain parenchyma, leading to death by 19–30 days postnatally. Transformed cells exhibited secondary structuring, a typical histopathological feature of human astrocytomas. Early passage cultures of these cells expressed GFAP in vitro and were transformed on the basis of tumor formation after transplantation into nude mice. These results demonstrate the susceptibility of periventricular astrocytic cells in the immature brain to malignant transformation. Furthermore, this study demonstrates the potential of the transgenic approach for the in vivo determination of genetic events involved in astrocyte transformation and for the development of novel models of astrocytoma.

¹ This work was supported by grants from the Anti-Cancer Council of Victoria, Stroke Research Foundation, Royal Australasian College of Surgeons, and the National Health and Medical Research Council of Australia.

² To whom requests for reprints should be addressed, at Department of Neurosurgery, The Children's Hospital, 300 Longwood Avenue, Boston, MA 02115.

Received 3/14/95. Accepted 7/17/95.

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