Soluble Neuregulin1 is a negative regulator of myelination

Peripheral nerves are characterized by the ability to regenerate after injury. The activity of Schwann cells is fundamental for all steps of peripheral nerve regeneration: immediately after injury they de-differentiate, remove myelin debris, proliferate and repopulate the injured nerve. Neuregulin1 (NRG1) is a factor strongly up-regulated and released by Schwann cells immediately after nerve injury, known to play an important role for their de-differentiation, proliferation and survival. Nevertheless, up to now, the global analysis of the genes regulated by NRG1 was not performed. For this reason, we planned a deep RNA sequencing to generate a transcriptome database and identify all the genes regulated following stimulation of primary adult rat Schwann cells with soluble recombinant NRG1. Interestingly, the gene ontology analysis of the transcriptome shows that NRG1 regulates genes belonging to categories strongly regulated in the peripheral nerve immediately following injury. In particular, NRG1 strongly inhibits the expression of genes involved in myelination and in glial cell differentiation, suggesting that NRG1 plays a fundamental role in the de-differentiation (or “trans-differentiation”) process of Schwann cells from a myelinating to a repair phenotype. Moreover, NRG1 inhibits genes involved in the apoptotic process, therefore promoting cell survival, and up-regulates genes positively regulating the ribosomal RNA processing, thus suggesting that NRG1 actively stimulates new protein expression. This transcriptome analysis demonstrates that NRG1, which is strongly up-regulated immediately after injury, drives the expression of many important genes, thus playing a major role in the regeneration process. Examination of genes regulated in Schwann cells after 6 hour stimulation with 10nM soluble Neuregulin1beta1

周围神经的标志性特征是损伤后具备再生能力。雪旺细胞（Schwann cells）的活性对于周围神经再生的所有步骤均至关重要：损伤发生后即刻，雪旺细胞即发生去分化，清除髓鞘碎片、增殖并重新填充受损神经区域。神经调节蛋白1（Neuregulin1, NRG1）是一类在神经损伤后即刻被雪旺细胞显著上调并释放的因子，已知其在雪旺细胞的去分化、增殖与存活过程中发挥关键作用。然而截至目前，尚未开展针对NRG1所调控基因的全基因组分析。为此，本研究计划通过深度RNA测序构建转录组数据库，以鉴定经可溶性重组NRG1刺激的原代成年大鼠雪旺细胞中所有受调控的基因。有趣的是，对该转录组的基因本体（Gene Ontology, GO）分析显示，NRG1所调控的基因类别与外周神经损伤后即刻受到显著调控的基因类别高度重合。具体而言，NRG1可强力抑制与髓鞘形成及胶质细胞分化相关的基因表达，这表明NRG1在雪旺细胞从髓鞘形成表型向修复表型的去分化（或“转分化”）过程中发挥核心作用。此外，NRG1可抑制参与细胞凋亡过程的基因表达，进而促进细胞存活；同时上调正向调控核糖体RNA加工的基因，提示NRG1可主动促进新蛋白质的合成。本转录组分析证实，损伤后即刻被大幅上调的NRG1可调控众多关键基因的表达，进而在再生过程中发挥主要作用。本研究同时对经10nM可溶性神经调节蛋白1β1刺激6小时后的雪旺细胞中的受调控基因进行了分析。