Transgenic mice expressing polyoma virus large T antigen in astrocytes develop severe dysmyelination of the central nervous system

Abstract

Transgenic mice were generated using a construct that encodes mouse polyoma virus large T antigen, one of three oncogenic products of the "early region" of the polyoma viral genome. Of 16 transgenic families developed, 1 was characterized by a neurologic disorder consisting of constant tremor and recurrent seizures. Morphologic analysis of the central nervous system (CNS) of affected transgenic mice included: classical light and electron microscopic examination; immunohistochemical assessment of the presence and localization of myelin-specific proteins, of the astrocyte marker glial fibrillary acidic protein, of the oligodendrocyte marker galactosyl cerebroside, and of large T; double immunolabeling of glial fibrillary acidic protein or galactosyl cerebroside and large T to identify the CNS cell type in which large T is expressed; and in situ hybridization to study myelin basic protein gene expression. Our results suggest that polyoma large T is expressed in astrocytes, possibly resulting in altered glial-glial interactions causing impaired oligodendroglial development and secondary dysmyelination. Transgenic oligodendrocytes exhibit features of immaturity, failing to myelinate axons properly and producing morphologic phenotypes of early stages of myelination, such as numerous mesaxonal profiles. Myelin proteins are markedly reduced in transgenic CNS, and myelin basic protein transcripts, while present, are generally decreased. We believe that expression of large T in astrocytes could influence the complex and dynamic interactions between astrocytes and oligodendrocytes, perhaps with regard to the molecular (trophic) signals in the local CNS environment, bringing about arrested oligodendroglial maturation and hypomyelination. This raises intriguing questions concerning the importance of glial-glial interactions in the CNS and the complex levels of control involved in biological expression of genetic information in glial cells.