Genetics Mechanisms of Myelination in Zebrafish

斑马鱼髓鞘形成的遗传学机制

• 批准号: 7057757
• 负责人: WILLIAM S TALBOT
• 金额: $ 35.23万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-02 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7057757
• 关键词: axon; cell cell interaction; cell differentiation; cell morphology; electron microscopy; functional /structural genomics; gene expression; gene mutation; genetic mapping; genetic regulation; genetic screening; genetically modified animals; glia; green fluorescent proteins; in situ hybridization; messenger RNA; molecular cloning; myelin; myelin basic proteins; myelination; neuroanatomy; neurogenesis; neurogenetics; neuroregulation; phenotype; reporter genes; zebrafish

DESCRIPTION (provided by applicant): This project will exploit the power of zebrafish genetics to discover new genes that are essential for myelination in the vertebrate nervous system. The myelin sheath wraps axons and allows for rapid transmission of action potentials in vertebrates. Disruption of myelin causes debilitating human diseases, including Multiple Sclerosis and hereditary neuropathies. Gaps in the understanding of the regulatory networks that govern the formation of myelinated axons have hindered progress toward therapies to repair myelin damage and prevent the loss of axons in affected nerves. To investigate the genetic mechanisms that control myelination, this project uses a zebrafish genetic screen to isolate mutations in genes with essential functions in the formation of myelinated axons. Preliminary studies have identified 13 mutations that :specifically disrupt the glial cells that form myelin. Initial phenotypic characterization suggests that two classes of mutants will be especially useful in the genetic dissection of myelination. (1) Seven mutations specifically disrupt myelinating glial cells in the peripheral nervous system, and in some cases axonal defects are also apparent. These mutations may represent zebrafish models of Charcot-Marie-Tooth disease and other hereditary neuropathies. (2) Myelinating glial cells in two other mutants have abnormal morphology, suggesting the hypothesis that these genes are essential for the terminal differentiation of myelinating glia. the specific aims of this project are (1) to isolate mutations in new genes with essential functions in myelination in an expanded genetic screen, (2) to define the functions of the mutated genes by analysis of glial development and myelin ultrastructure in the mutants, and (3) to discover the biochemical basis of the genes' function in myelination by molecular analysis of the mutations. This project will define new zebrafish models of important myelin disorders in human, discover new genes with essential functions in myelination, and provide new avenues toward therapies for myelin repair and prevention of axonal damage after demyelination.

描述（由申请人提供）：该项目将利用斑马鱼遗传学的力量来发现对脊椎动物神经系统髓鞘形成至关重要的新基因。髓鞘包裹轴突并允许脊椎动物动作电位的快速传输。髓磷脂的破坏会导致使人衰弱的疾病，包括多发性硬化症和遗传性神经病。对控制有髓轴突形成的调节网络的理解存在差距，阻碍了修复髓鞘损伤和防止受影响神经中轴突丢失的疗法的进展。为了研究控制髓鞘形成的遗传机制，该项目使用斑马鱼遗传筛选来分离在有髓鞘轴突形成中具有重要功能的基因突变。初步研究已确定 13 种突变：特异性破坏形成髓磷脂的神经胶质细胞。最初的表型表征表明，两类突变体在髓鞘形成的遗传解剖中特别有用。 (1) 七种突变特异性破坏周围神经系统中的髓鞘神经胶质细胞，在某些情况下轴突缺陷也很明显。这些突变可能代表夏科-玛丽-图斯病和其他遗传性神经病的斑马鱼模型。 (2)另外两个突变体中的髓鞘神经胶质细胞具有异常形态，这表明这些基因对于髓鞘神经胶质细胞的终末分化是必需的。该项目的具体目标是（1）在扩大的遗传筛选中分离出在髓鞘形成中具有重要功能的新基因的突变，（2）通过分析突变体中的神经胶质发育和髓磷脂超微结构来定义突变基因的功能， (3)通过突变的分子分析来发现基因在髓鞘形成中的功能的生化基础。该项目将定义人类重要髓鞘疾病的新斑马鱼模型，发现在髓鞘形成中具有重要功能的新基因，并为髓鞘修复和预防脱髓鞘后轴突损伤的治疗提供新途径。