星形胶质细胞TOX3调控髓鞘发育的新发现及机制研究

髓鞘发育的完整性保证了神经系统准确有效的信息传递，星形胶质细胞如何调控髓鞘发育是神经科学领域的重要问题。TOX3是中枢神经系统发育中含HMG-box结构域的重要转录因子。本课题首次构建了TOX3星形胶质细胞条件性敲除小鼠，前期发现其运动功能明显受损，且脑白质髓鞘数量减低，髓鞘结构紊乱，少突胶质前体细胞增殖分化能力减低。本课题拟在前期基础上，利用免疫荧光、透射电镜及RNA-seq等技术，探讨星形胶质细胞TOX3在调控少突胶质细胞发育及髓鞘形成中的作用，并从生长因子、脂质代谢等方面分析TOX3对胶质细胞间交互对话的作用，结合外泌体研究建立星形胶质细胞调控髓鞘发育新机制。构建以TOX3为中心的转录因子、下游靶基因及表观遗传因子的多层次调控网络。本课题构建了研究星形胶质细胞调控髓鞘发育的良好动物模型，并深入探究星形胶质细胞TOX3在髓鞘发育中的作用机制，为临床脑白质发育相关疾病的治疗提供新的思路。

The integrity of myelin guarantees accurate and effective information transmission in the central nervous system. The study of astrocytes regulating myelination is an important issue in the field of neuroscience. TOX3 is an important transcription factor containing a high mobility group (HMG)-box domain. Our preliminary data demonstrated that the TOX3 astrocyte conditional knockout mice showed significant impaired motor function. Histological analysis showed that the number of white matter myelin was reduced with disordered structure. The use of qPCR, WB and other techniques indicated that the proliferation and differentiation of oligodendrocytes are inhibited. On the basis of above findings, this project will use immunofluorescence staining, TEM, ChIP-seq analysis and RNA-seq analysis to identify the role and mechanisms of astrocyte TOX3 in oligodendrocytes development and myelination. We will detect the effect of TOX3 on glial cells crosstalk from the aspects of growth factors and lipid metabolism, and establish a new mechanism of astrocytes regulating myelination with exosome research. A TOX3-centric regulatory network of important transcription factors, target genes and epigenetic factors will be constructed. This study creates a mouse model for studying oligodendrocyte development and myelination, and explores the mechanisms of astrocyte TOX3 regulation, throwing lights on future strategies in the treatment of clinical white matter diseases.