A transgenic mouse model for trilateral retinoblastoma
J. M. O'Brien, D. M. Marcus, R. Bernards, J. L. Carpenter, J. J. Windle, P. Mellon and D. M. Albert
Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston 02114.
We present a murine model of trilateral retinoblastoma. Ocular
retinoblastoma and central nervous system tumors are observed in a line of
mice formed by the transgenic expression of SV40 T-antigen. An oncogenic
protein known to bind to the retinoblastoma gene product (p105-Rb) is
specifically expressed within retinal cells in this model. All animals that
carry this genetic alteration develop multifocal retinal tumors. Midbrain
tumors are observed in 15% of ocular tumor-bearing animals, and these arise
ventral to the cerebral aqueduct at the level of the pineal gland. Both
ocular and central nervous system neoplasms are heritable in heterozygous
offspring through 10 sequential generations of breeding. Retinal tumors
display the gross appearance, invasive properties, light and electron
microscopic features, and immunohistochemical staining characteristics of
human retinoblastoma. The light and electron microscopic characteristics as
well as immunocytochemical features of undifferentiated midline central
nervous system neoplasms further correlate with human trilateral
retinoblastoma. We postulate an alternative mechanism of retinoblastoma
tumorigenesis that involves functional inactivation of retinoblastoma
protein locally in the face of an intact retinoblastoma gene locus.
