Knockdown of Dock7 <i>in vivo</i>specifically affects myelination by Schwann cells and increases myelin thickness in sciatic nerves without affecting axon thickness

• 作者: Akito Tanoue Hideki Tsumura Junji Yamauchi Kazuaki Nakamura Masahiro Maeda Motoshi Nagao Naoko Onami Tomohiro Torii Yuki Miyamoto
• 来源期刊: 美国分子生物学期刊(英文)
• 学科: 医学
• 关键词: Dock7 Transgenic Mouse Schwann Cell MYELINATION AXON Diameter
• 年，卷（期）: 2012,（3）
• 页码范围: 210-216
• 页数: 7页
• 分类号: R73

摘要

During development of the peripheral nervous system (PNS), Schwann cells (SCs) wrap individual axons to form myelin sheaths, which act as surrounding insulators and markedly enhance the propagation of the action potential. In peripheral neuropathies such as Guillain-Barré syndrome (GBS) and inherited demyelinating Charcot-Marie-Tooth (CMT) disease and diabetic neuropathies, chronic demyelination and defective remyelination are repeated, causing more severe neuropathies. It is thus thought that development of a drug that promotes proper myelination with minimal side effects could provide an effective therapy for these diseases. As yet, however, little is known about therapeutic target molecules and genetically-modified mice for testing such approaches. We previously cloned the dock7 gene and characterized Dock7 as the regulator controlling SC myelination;however, an important issue, whether knockdown of Dock7 specifically affects myelination by SCs but not leaves neurons unaffected, has remained unclear. Here, we generate newly-produced transgenic mice harboring short-hairpin RNA (shRNA) targeting Dock7. We also describe that Dock7 shRNA transgenic mice exhibit enhanced myelin thickness without affecting axon thickness in sciatic nerves of the PNS, as reduced thickness of the axon diameter is the primary indicator of denatured neurons. Similarly, purified in vitro SC-neuronal cocultures established from transgenic mice exhibit enhanced formation of myelin segments, suggesting that knockdown of Dock7 promotes myelination by SCs. Collectively, Dock7 knockdown specifically affects SC myelination in sciatic nerves, providing evidence that Dock7 may be a promising drug-target-specific molecules for developing a therapy for peripheral neuropathies that aims to enhance myeliantion.