Mechanisms of Developmental Myelination

项目摘要 这项研究计划的长期目标是了解发育中的中枢神经系统的特定轴突是如何在神经元中表达的。 神经系统（CNS）被特定数量的髓鞘包裹，髓鞘是一种专门的，富含蛋白脂质的 由少突胶质细胞产生的膜。在发育过程中，神经祖细胞的亚群产生 少突胶质细胞前体细胞（OPC），其迁移和分裂以填充CNS。随后，一些 OPCs分化为髓鞘少突胶质细胞，而其他OPCs持续到成年。 重要的是，髓磷脂是可塑的，可以通过大脑活动进行修改。最近的证据表明， OPC增殖，少突胶质细胞分化，髓鞘特征和轴突选择， 髓鞘形成有助于髓鞘可塑性。然而，调节髓鞘形成的分子机制， 特别是对神经元活动的反应，知之甚少。包括这件事的调查 研究计划集中在发展髓鞘形成的三个广泛领域。首先，使用单细胞RNA-seq 我们生成的数据，我们将研究神经祖细胞是如何被指定为OPC的。第二，将轴胶质 相互作用和mRNA定位促进髓鞘生长。第三，我们将研究小胶质细胞， CNS的固有免疫细胞响应于神经元活动而改变轴突上的髓鞘覆盖。 我们使用斑马鱼作为模型系统，这使我们能够将联合收割机延时成像与遗传和 药理学操作以观察和测试完整的活动物中的细胞行为和髓鞘形成。 这项研究计划的结果有可能为发展提供重要的新见解， 学习，记忆和精神疾病的基础，并为设计治疗方案提供基础。 促进因疾病或损伤而受损的大脑髓鞘形成的策略。

PROJECT SUMMARY The long-term goal of this research program is to understand how specific axons of the developing central nervous system (CNS) are ensheathed with specific amounts of myelin, a specialized, proteolipid-rich membrane produced by oligodendroglia. During development, subpopulations of neural progenitors produce oligodendrocyte precursor cells (OPCs), which migrate and divide to populate the CNS. Subsequently, some OPCs differentiate as myelinating oligodendrocytes whereas other OPCs persist through adulthood. Importantly, myelin is plastic and can be modified by brain activity. Recent evidence indicates that changes in OPC proliferation, oligodendrocyte differentiation, myelin sheath characteristics and axon selection for myelination contribute to myelin plasticity. However, the molecular mechanisms that regulate myelination, particularly in response to neuronal activity, are poorly understood. The investigations that comprise this research program focus on three broad areas of developmental myelination. First, using single cell RNA-seq data we generated, we will investigate how neural progenitors are specified as OPCs. Second, will axo-glial interactions and mRNA localization promote myelin sheath growth. Third, we will investigate how microglia, the resident innate immune cells of the CNS, modify myelin coverage on axons in response to neuronal activity. We use zebrafish as a model system, which enables us to combine time-lapse imaging with genetic and pharmacological manipulations to observe and test cell behaviors and myelination in an intact, living animal. The results of this research program have the potential to provide important new insights to the developmental basis of learning, memory and psychiatric disease and to provide a foundation for designing therapeutic strategies to promote myelination of brains damaged by disease or injury.