Abstract：
Myelination is the terminal step in a complex and precisely timed program that orchestrates the proliferation, migration and differentiation of oligodendroglial cells. It is thought that Sonic Hedgehog (Shh) acting on Smoothened (Smo) participates in regulating this process, but that these effects are highly context dependent. Here, we investigate oligodendroglial development and remyelination from three specific transgenic lines: NG2-CreERT2 (control), Smofl/fl/NG2-CreERT2 (loss of function), and SmoM2/NG2-CreERT2 (gain of function), as well as pharmacological manipulation that enhance or inhibit the Smo pathway (Smoothened Agonist (SAG) or cyclopamine treatment, respectively). To explore the effects of Shh/Smo on differentiation and myelination in vivo, we developed a highly quantifiable model by transplanting oligodendrocyte precursor cells (OPCs) in the retina. We find that myelination is greatly enhanced upon cyclopamine treatment and hypothesize that Shh/Smo could promote OPC proliferation to subsequently inhibit differentiation. Consistent with this hypothesis, we find that the genetic activation of Smo significantly increased numbers of OPCs and decreased oligodendrocyte differentiation when we examined the corpus callosum during development and after cuprizone demyelination and remyelination. However, upon loss of function with the conditional ablation of Smo, myelination in the same scenarios are unchanged. Taken together, our present findings suggest that the Shh pathway is sufficient to maintain OPCs in an undifferentiated state, but is not necessary for myelination and remyelination.
摘要：
髓鞘形成是一个复杂且精确定时的程序中的最终步骤，它协调了增殖，少突胶质细胞的迁移和分化。据认为，作用于Smo（Smo）的SonicHedgehog（Shh）参与调节这一过程，但是这些影响高度依赖于上下文。这里,我们研究了三种特定转基因系的少突胶质细胞发育和髓鞘再生：NG2-CreERT2（对照），Smofl/fl/NG2-CreERT2（功能丧失），和SmoM2/NG2-CreERT2（功能增益），以及增强或抑制Smo途径的药理学操作（平滑激动剂（SAG）或环巴胺治疗，分别)。探讨Shh/Smo对体内分化和髓鞘形成的影响,我们通过在视网膜中移植少突胶质前体细胞(OPCs)建立了一个高度可量化的模型.我们发现，在环巴胺治疗后，髓鞘形成大大增强，并假设Shh/Smo可以促进OPC增殖，从而抑制分化。与这个假设一致，我们发现，当我们在发育过程中以及铜宗脱髓鞘和髓鞘再生后检查call体时，Smo的遗传激活显着增加了OPCs的数量，并减少了少突胶质细胞的分化。然而,在Smo有条件消融的情况下失去功能时，髓鞘形成在相同的情况下是不变的。一起来看,我们目前的研究结果表明，Shh途径足以维持OPCs处于未分化状态，但不是髓鞘形成和髓鞘再生所必需的。
