Regional hypomyelination and dysplasia in transgenic mice with astrocyte-directed expression of interferon-γ
Regional hypomyelination and dysplasia in transgenic mice with astrocyte-directed expression of interferon-γ
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DOI：
10.1385/jmn:15:1:45
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发表时间：
2000-08-01
影响因子：
3.1
通讯作者：
Leissring, MA
中科院分区：
文献类型：
--
作者：
LaFerla, FM;Sugarman, MC;Leissring, MA
干扰素- γ (ifn - γ)，传统上与免疫系统的多种生理和病理过程有关，对神经系统细胞表现出一系列生物学效应。临床和体外研究支持ifn - γ在免疫介导的脱髓鞘疾病（如多发性硬化症（MS））发病机制中的关键作用。为了研究该细胞因子在中枢神经系统（CNS）中的作用，我们培育了转基因小鼠，其中ifn - γ转基因表达选择性地靶向星形胶质细胞，这是该细胞因子的潜在重要细胞来源。在这里，我们报告了星形胶质细胞导向的ifn - γ的表达导致区域性的髓鞘退化和脑组织发生的选择性破坏，其中包括严重的小脑和海马发育不良。转基因小鼠明显共济失调，多数在性成熟前死亡。本研究表明，星形胶质细胞导向的ifn - γ表达深刻影响大脑的分化和形态发生，并提供了额外的证据，证明这种细胞因子对髓磷脂生成细胞具有有害的后果，而不依赖于细胞来源。
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.