Ablation of Dicer from murine Schwann cells increases their proliferation while blocking myelination

The myelin sheaths that surround the thick axons of the peripheral nervous system are produced by the highly specialized Schwann cells. Differentiation of Schwann cells and myelination occur in discrete steps. Each of these requires coordinated expression of specific proteins in a precise sequence, yet the regulatory mechanisms controlling protein expression during these events are incompletely understood. Here we report that Schwann cell-specific ablation of the enzyme Dicer1, which is required for the production of small non-coding regulatory microRNAs, fully arrests Schwann cell differentiation, resulting in early postnatal lethality. Dicer-/- Schwann cells had lost their ability to myelinate, yet were still capable of sorting axons. Both cell death and, paradoxically, proliferation of immature Schwann cells was vastly enhanced, suggesting that their terminal differentiation is triggered by growth-arresting regulatory microRNAs. Using microRNA microarrays, we identified 16 miRNAs that are upregulated upon myelination and whose expression is controlled by Dicer in Schwann cells. This set of microRNAs appears to drive Schwann cell differentiation and myelination of peripheral nerves, thereby fulfilling a crucial function for survival of the organism. Samples representing Schwann cell-specific ablation of the enzyme Dicer1 and wild type controls at developmental stages E17 and P4. Geometric mean-averaged data linked below as supplementary file.包裹外周神经系统粗大轴突的髓鞘由高度特化的施万细胞（Schwann cells）生成。施万细胞的分化与髓鞘形成过程分步进行，每一步均需特定蛋白质按精确时序协同表达，但调控此类过程中蛋白质表达的分子机制尚未完全阐明。本文报道，对生成小型非编码调控微RNA（microRNAs, miRNAs）所必需的Dicer1酶进行施万细胞特异性敲除，可完全阻断施万细胞分化，进而导致出生后早期致死。Dicer1基因缺失的施万细胞丧失了髓鞘形成能力，但仍可完成轴突分选。未成熟施万细胞的细胞死亡与增殖（反常的是）均显著增强，这提示终末分化由生长阻滞型调控微RNA所触发。通过微RNA芯片分析，我们鉴定出16种在髓鞘形成过程中上调、且在施万细胞中受Dicer1调控的微RNA。该组微RNA似乎可驱动施万细胞分化与外周神经髓鞘形成，从而为机体存活发挥关键作用。本研究样本涵盖胚胎期17天（E17）与出生后第4天（P4）两个发育阶段的施万细胞特异性Dicer1敲除样本及野生型对照样本，经几何均值平均化处理的相关数据详见下文补充文件。