Dicer in Schwann Cells Is Required for Myelination and Axonal Integrity
Dicer in Schwann Cells Is Required for Myelination and Axonal Integrity
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DOI：
10.1523/jneurosci.0801-10.2010
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发表时间：
2010-05-12
影响因子：
5.3
通讯作者：
Suter, Ueli
中科院分区：
文献类型：
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作者：
Pereira, Jorge A.;Baumann, Reto;Suter, Ueli
Dicer负责生成成熟的微rna （mirna）并将其装载到rna诱导沉默复合体（RISC）中。RISC作为靶向mRNA的探针，导致翻译抑制和mRNA降解。周围神经系统中的雪旺细胞（SCs）在向髓鞘化和非髓鞘化表型的谱系进展过程中，在形态和基因表达模式上都经历了显著的分化。SCs中的基因表达受到特别严格的调控，对生物体至关重要，一些髓磷脂蛋白（如PMP22）的正常基因表达减少50%或增加至150%，会导致周围神经病变。在这里，我们选择性地从小家鼠SCs中删除了Dicer，并因此删除了成熟mirna对基因表达的调控。我们的研究结果表明，在没有Dicer的情况下，大多数sc在早髓鞘形成阶段停止，不能开始形成髓磷脂。在分子水平上，早髓鞘转录因子Krox20和几种髓鞘蛋白[包括髓鞘相关糖蛋白（myelin associated glycoprotein， MAG）和PMP22]在突变的坐骨神经中显著降低。相比之下，髓鞘形成抑制剂SOX2、Notch1和Hes1增加，为髓鞘形成受损提供了额外的潜在基础。一小部分SCs，在感觉纤维和运动纤维之间存在一些特殊的差异，克服了髓鞘阻滞，形成了异常薄的髓鞘，这与观察到的受损的神经调节蛋白和AKT信号一致。令人惊讶的是，我们还在Dicer突变小鼠中发现了轴突变性的迹象。因此，我们的数据表明，mirna对雪旺细胞基因表达的调控至关重要，这是髓鞘形成和通过轴突-胶质相互作用维持轴突所必需的。
Dicer is responsible for the generation of mature micro-RNAs (miRNAs) and loading them into RNA-induced silencing complex (RISC). RISC functions as a probe that targets mRNAs leading to translational suppression and mRNA degradation. Schwann cells (SCs) in the peripheral nervous system undergo remarkable differentiation both in morphology and gene expression patterns throughout lineage progression to myelinating and nonmyelinating phenotypes. Gene expression in SCs is particularly tightly regulated and critical for the organism, as highlighted by the fact that a 50% decrease or an increase to 150% of normal gene expression of some myelin proteins, like PMP22, results in peripheral neuropathies. Here, we selectively deleted Dicer and consequently gene expression regulation by mature miRNAs from Mus musculus SCs. Our results show that in the absence of Dicer, most SCs arrest at the promyelinating stage and fail to start forming myelin. At the molecular level, the promyelinating transcription factor Krox20 and several myelin proteins [including myelin associated glycoprotein (MAG) and PMP22] were strongly reduced in mutant sciatic nerves. In contrast, the myelination inhibitors SOX2, Notch1, and Hes1 were increased, providing an additional potential basis for impaired myelination. A minor fraction of SCs, with some peculiar differences between sensory and motor fibers, overcame the myelination block and formed unusually thin myelin, in line with observed impaired neuregulin and AKT signaling. Surprisingly, we also found signs of axonal degeneration in Dicer mutant mice. Thus, our data indicate that miRNAs critically regulate Schwann cell gene expression that is required for myelination and to maintain axons via axon-glia interactions.