Department of Pharmacology and Laboratory Animal Resource Facility, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
J Neurosci. 2011 Aug 31;31(35):12579-92. doi: 10.1523/JNEUROSCI.2738-11.2011.
In development of the peripheral nervous system, Schwann cells proliferate, migrate, and ultimately differentiate to form myelin sheath. In all of the myelination stages, Schwann cells continuously undergo morphological changes; however, little is known about their underlying molecular mechanisms. We previously cloned the dock7 gene encoding the atypical Rho family guanine-nucleotide exchange factor (GEF) and reported the positive role of Dock7, the target Rho GTPases Rac/Cdc42, and the downstream c-Jun N-terminal kinase in Schwann cell migration (Yamauchi et al., 2008). We investigated the role of Dock7 in Schwann cell differentiation and myelination. Knockdown of Dock7 by the specific small interfering (si)RNA in primary Schwann cells promotes dibutyryl cAMP-induced morphological differentiation, indicating the negative role of Dock7 in Schwann cell differentiation. It also results in a shorter duration of activation of Rac/Cdc42 and JNK, which is the negative regulator of myelination, and the earlier activation of Rho and Rho-kinase, which is the positive regulator of myelination. To obtain the in vivo evidence, we generated Dock7 short hairpin (sh)RNA transgenic mice. They exhibited a decreased expression of Dock7 in the sciatic nerves and enhanced myelin thickness, consistent with in vitro observation. The effects of the in vivo knockdown on the signals to Rho GTPases are similar to those of the in vitro knockdown. Collectively, the signaling through Dock7 negatively regulates Schwann cell differentiation and the onset of myelination, demonstrating the unexpected role of Dock7 in the interplay between Schwann cell migration and myelination.
在周围神经系统的发育过程中，许旺细胞增殖、迁移，并最终分化形成髓鞘。在所有的髓鞘形成阶段，许旺细胞不断经历形态变化；然而，其潜在的分子机制知之甚少。我们之前克隆了编码非典型 Rho 家族鸟嘌呤核苷酸交换因子（GEF）的 dock7 基因，并报道了 Dock7、其靶 Rho GTPases Rac/Cdc42 和下游 c-Jun N-末端激酶在许旺细胞迁移中的积极作用（Yamauchi 等人，2008）。我们研究了 Dock7 在许旺细胞分化和髓鞘形成中的作用。在原代许旺细胞中，特异性小干扰（si）RNA 敲低 Dock7 可促进二丁酰环腺苷酸诱导的形态分化，表明 Dock7 在许旺细胞分化中起负调控作用。它还导致 Rac/Cdc42 和 JNK 的激活时间缩短，而 Rac/Cdc42 和 JNK 是髓鞘形成的负调控因子， Rho 和 Rho-kinase 的激活时间更早，而 Rho 和 Rho-kinase 是髓鞘形成的正调控因子。为了获得体内证据，我们生成了 Dock7 短发夹（sh）RNA 转基因小鼠。它们在坐骨神经中表现出 Dock7 表达降低，并且髓鞘厚度增加，与体外观察一致。体内敲低对 Rho GTPases 信号的影响与体外敲低的影响相似。总之，通过 Dock7 传递的信号负调节许旺细胞分化和髓鞘形成的开始，表明 Dock7 在许旺细胞迁移和髓鞘形成之间的相互作用中具有意想不到的作用。
