Pogoda Hans-Martin, Sternheim Nitzan, Lyons David A, Diamond Brianne, Hawkins Thomas A, Woods Ian G, Bhatt Dimple H, Franzini-Armstrong Clara, Dominguez Claudia, Arana Naomi, Jacobs Jennifer, Nix Rebecca, Fetcho Joseph R, Talbot William S
Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Dev Biol. 2006 Oct 1;298(1):118-31. doi: 10.1016/j.ydbio.2006.06.021. Epub 2006 Jun 15.
The myelin sheath insulates axons in the vertebrate nervous system, allowing rapid propagation of action potentials via saltatory conduction. Specialized glial cells, termed Schwann cells in the PNS and oligodendrocytes in the CNS, wrap axons to form myelin, a compacted, multilayered sheath comprising specific proteins and lipids. Disruption of myelinated axons causes human diseases, including multiple sclerosis and Charcot-Marie-Tooth peripheral neuropathies. Despite the progress in identifying human disease genes and other mutations disrupting glial development and myelination, many important unanswered questions remain about the mechanisms that coordinate the development of myelinated axons. To address these questions, we began a genetic dissection of myelination in zebrafish. Here we report a genetic screen that identified 13 mutations, which define 10 genes, disrupting the development of myelinated axons. We present the initial characterization of seven of these mutations, defining six different genes, along with additional characterization of mutations that we have described previously. The different mutations affect the PNS, the CNS, or both, and phenotypic analyses indicate that the genes affect a wide range of steps in glial development, from fate specification through terminal differentiation. The analysis of these mutations will advance our understanding of myelination, and the mutants will serve as models of human diseases of myelin.
髓鞘可使脊椎动物神经系统中的轴突绝缘，从而通过跳跃式传导实现动作电位的快速传播。在周围神经系统（PNS）中称为施万细胞、在中枢神经系统（CNS）中称为少突胶质细胞的特殊神经胶质细胞会包裹轴突以形成髓鞘，髓鞘是一种由特定蛋白质和脂质组成的紧密多层鞘。有髓轴突的破坏会引发人类疾病，包括多发性硬化症和夏科-马里-图斯周围神经病。尽管在鉴定人类疾病基因以及其他破坏神经胶质细胞发育和髓鞘形成的突变方面取得了进展，但关于协调有髓轴突发育的机制仍存在许多重要的未解问题。为了解决这些问题，我们开始对斑马鱼的髓鞘形成进行遗传学剖析。在此，我们报告了一项遗传筛选，该筛选鉴定出13个突变，这些突变定义了10个基因，它们破坏了有髓轴突的发育。我们展示了其中7个突变的初步特征，定义了6个不同的基因，同时还对我们之前描述过的突变进行了补充特征描述。不同的突变影响PNS、CNS或两者，表型分析表明这些基因影响神经胶质细胞发育的广泛步骤，从命运决定到终末分化。对这些突变的分析将增进我们对髓鞘形成的理解，并且这些突变体将作为人类髓鞘疾病的模型。
