Persistent astrocyte activation in the fragile X mouse cerebellum.
Persistent astrocyte activation in the fragile X mouse cerebellum.
复制标题
脆弱的X小鼠小脑中持续的星形胶质细胞激活。
DOI：
10.1002/brb3.400
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发表时间：
2015-10
影响因子：
3.1
通讯作者：
Hampson DR
中科院分区：
文献类型：
--
作者：
Pacey LK;Guan S;Tharmalingam S;Thomsen C;Hampson DR
脆性 X 综合征是自闭症最常见的单基因病因，是由 RNA 结合蛋白 FMRP 缺失引起的。尽管 FMRP 在神经元中高度表达，但最近也在神经胶质细胞中被发现。据推测，在没有 FMRP 的情况下，非神经元细胞的异常功能可能导致该疾病的发病机制。我们之前证明了脆性 X (Fmr1) 敲除小鼠小脑中少突胶质细胞前体细胞数量减少和髓鞘形成延迟。我们使用定量蛋白质印迹和免疫细胞化学来检查 Fmr1 小鼠在发育和成年期间小脑中星形胶质细胞和小胶质细胞的状态。我们报告 Fmr1 小鼠小脑中星形胶质细胞标记物 GFAP 的表达增加，从出生后第二周开始一直持续到成年。出生后 2 周，Fmr1 KO 小脑中肿瘤坏死因子受体 2 (TNFR2) 和白血病抑制因子 (LIF) 的表达升高。在成人中，Fmr1 敲除小鼠中 TNFR2 和神经胶质标记物 S100β 的表达也有所升高，但 LIF 的表达与野生型小鼠没有差异。我们在任何年龄的检查中都没有发现小胶质细胞激活或神经炎症的证据。这些发现表明，在 Fmr1 敲除小鼠小脑中，在没有小胶质细胞激活的情况下，存在一种非典型的星形胶质细胞增生模式。年轻小鼠中 TNFR2 和 LIF 表达的增强表明，星形胶质细胞蛋白表达的变化可能是为了补偿 Fmr1 小鼠发育中小脑的髓鞘形成延迟。
Fragile X Syndrome, the most common single gene cause of autism, results from loss of the RNA‐binding protein FMRP. Although FMRP is highly expressed in neurons, it has also recently been identified in glia. It has been postulated that in the absence of FMRP, abnormal function of non‐neuronal cells may contribute to the pathogenesis of the disorder. We previously demonstrated reduced numbers of oligodendrocyte precursor cells and delayed myelination in the cerebellum of fragile X (Fmr1) knockout mice. We used quantitative western blotting and immunocytochemistry to examine the status of astrocytes and microglia in the cerebellum of Fmr1 mice during development and in adulthood. We report increased expression of the astrocyte marker GFAP in the cerebellum of Fmr1 mice starting in the second postnatal week and persisting in to adulthood. At 2 weeks postnatal, expression of Tumor Necrosis Factor Receptor 2 (TNFR2) and Leukemia Inhibitory Factor (LIF) were elevated in the Fmr1 KO cerebellum. In adults, expression of TNFR2 and the glial marker S100β were also elevated in Fmr1 knockouts, but LIF expression was not different from wild‐type mice. We found no evidence of microglial activation or neuroinflammation at any age examined. These findings demonstrate an atypical pattern of astrogliosis in the absence of microglial activation in Fmr1 knockout mouse cerebellum. Enhanced TNFR2 and LIF expression in young mice suggests that changes in the expression of astrocytic proteins may be an attempt to compensate for delayed myelination in the developing cerebellum of Fmr1 mice.