Evaluation of a drug-target-molecule for demyelinating disorders using Dock7 knockdown mouse

在周围神经系统（PNS）的发育过程中，许旺细胞（SC）包裹轴突形成称为髓鞘的多层结构，其功能是作为轴突周围的绝缘体。在周围神经病变如腓骨肌萎缩症（CMT）中，慢性脱髓鞘和髓鞘再生缺陷反复发生，导致更严重的神经病变。因此，人们认为，开发一种促进健康髓鞘形成的药物，副作用最小，可能会导致这些疾病的有用的治疗方法。然而，迄今为止，促进髓鞘形成的特定治疗药物靶点仍然不清楚。在这项研究中，我们产生了新的转基因小鼠，表达Dock7的shRNA，敲低Dock7蛋白水平。我们描述了敲除Dock7在体内和体外特异性地促进髓鞘形成。据我们所知，这是第一次报道一种可能的治疗靶分子，促进髓鞘形成而不减少轴突厚度。

During development of the peripheral nervous system (PNS), Schwann cells (SCs) wrap axons to form a multilamellar structure called myelin, which functions as an insulator surrounding axons. In peripheral neuropathies such as Charcot-Marie-Tooth (CMT) disease, chronic demyelination and defective remyelination are repeated, causing more severe neuropathies. It is thus thought that development of a drug that promotes healthy myelination, with minimal side effects, may lead to useful therapeutic methods for these diseases. However, specific therapeutic drug targets that healthily promote myelination have hitherto remained unclear. In this study, we generated new transgenic mice expressing shRNA for Dock7, which knocked down Dock7 protein levels. We describe that knockdown of Dock7 specifically promotes myelination in vivo and in vitro. To the best of our knowledge, this is the first report of a possible therapeutic target molecule that promotes myelination without reduced axon thickness.