多巴胺对脊髓少突胶质细胞发育分化的时空调控及作用机制

中枢神经系统中，少突胶质细胞(OLs)包绕轴突形成髓鞘，髓鞘对神经元信息的快速电传导具有重要意义。由髓鞘发育障碍或再生障碍引起的如髓鞘形成不良症、多发性硬化症等疾病皆与少突胶质细胞前体细胞(OPCs)不能有效分化为OLs有关，然而OLs的发育分化机制尚未完全清楚。脊髓OPCs的分化与多巴胺信号的下行投射在时间上和空间上高度一致,且我们前期研究发现多巴胺抑制剂可以特异性影响斑马鱼髓鞘形成，故推测多巴胺可时空调控OPCs的分化。本研究拟以斑马鱼为实验模型，利用显微成像技术明确多巴胺及其受体在OPCs中的时空表达，并通过多巴胺缺陷型突变体模型验证多巴胺对OPCs的分化作用。通过转录组分析结合基因敲除或过表达技术系统性筛选鉴定多巴胺下游的分子，阐明多巴胺调控OPCs分化的机制。此研究将揭示胞外信号与胞内分子对OLs发育的协同调控机制，并为髓鞘形成不良和多发性硬化症等疾病的治疗提供新的分子靶标。

Oligodendrocytes make myelin sheets by wrapping axons, which is critical for electrical signal transmission. Diseases with myelination or remyelination defects, including but not limit to leukodystrophy and multiple sclerosis mainly attribute to inefficient differentiation of oligodendrocyte progenitor cells (OPCs). However, the molecular mechanism in oligodendrocyte differentiation is not clear. In the spinal cord, oligodendrocyte differentiation moves anteriorly to posteriorly, highly orchestrated with dopamine descending signals. Our previous study showed that dopamine neurotoxin could specifically disturb oligodendrocyte differentiation in zebrafish. We predict that dopamine temporally and spatially regulates oligodendrocyte differentiation. In this study, we will characterize the distribution or expression pattern of dopamine and its receptors in oligodendrocyte progenitor cells with microscopy and use dopamine-deficient fish line to confirm the role of dopamine in oligodendrocyte differentiation. We will further systematically analyze the downstream signaling involved in dopamine pathway with RNA-seq and confirm the results with CRISPR or mRNA overexpression. This study will help us understand how extracellular signals coordinate intracellular molecules to regulate oligodendrocyte development, and this study will provide insight on the molecular therapeutic targets of leukodystrophy and demyelination.