Regional hypomyelination and dysplasia in transgenic mice with astrocyte-directed expression of interferon-gamma

Interferon-gamma (IFN-gamma), traditionally associated with a variety of physiological and pathological processes of the immune system, manifests an array of biological effects on cells of the nervous system. Clinical and in vitro studies support a key role for IFN-gamma in the pathogenesis of immun...

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Bibliographic Details
Published in:Journal of molecular neuroscience 2000-08, Vol.15 (1), p.45-60
Main Authors: LaFerla, F M, Sugarman, M C, Lane, T E, Leissring, M A
Format: Article
Language:English
Subjects:
Animals
Astrocytes - metabolism
Brain - abnormalities
Brain - metabolism
Brain - physiopathology
Cell Death - genetics
Cerebellum - abnormalities
Cerebellum - metabolism
Cerebellum - physiopathology
Demyelinating Autoimmune Diseases, CNS - genetics
Demyelinating Autoimmune Diseases, CNS - metabolism
Demyelinating Autoimmune Diseases, CNS - physiopathology
Genes, Regulator - physiology
Glial Fibrillary Acidic Protein - genetics
Hippocampus - abnormalities
Hippocampus - metabolism
Hippocampus - physiopathology
Interferon-gamma - genetics
Interferon-gamma - metabolism
Mice
Mice, Transgenic
Nerve Fibers, Myelinated - metabolism
Nerve Fibers, Myelinated - pathology
Tumor Necrosis Factor-alpha - genetics
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Summary:Interferon-gamma (IFN-gamma), traditionally associated with a variety of physiological and pathological processes of the immune system, manifests an array of biological effects on cells of the nervous system. Clinical and in vitro studies support a key role for IFN-gamma in the pathogenesis of immune-mediated demyelinating disorders such as multiple sclerosis (MS). To investigate the role of this cytokine within the central nervous system (CNS), transgenic mice were derived in which IFN-gamma transgene expression was selectively targeted to astrocytes, a potentially important cellular source of this cytokine. Here we report that astrocyte-directed expression of IFN-gamma results in regional hypomyelination and selective disruption of brain histogenesis, which included severe cerebellar and hippocampal dysplasia. Transgenic mice were markedly ataxic and the majority died prior to reaching sexual maturity. This study demonstrates that astrocyte-directed expression of IFN-gamma profoundly affects the differentiation and morphogenesis of the brain and provides additional evidence that this cytokine has deleterious consequences on myelin-producing cells, independent of the cellular source.
ISSN:0895-8696
1559-1166
0895-8696
DOI:10.1385/JMN:15:1:45