Gab在中枢神经系统髓鞘发育与髓鞘损伤修复中的功能及其机制

Oligodendrocytes (OLs) form myelin in the central nervous system. Myelin defect is one of important symptoms in many brain diseases, such as multiple sclerosis, white matter injury, autism and schizophrenia. The proliferation of oligodendrocyte precursor cells (OPCs) and their timely differentiation into mature OLs play critical roles in myelination. Although previous studies show that the myelination is regulated by multiple cell-intrinsic and extracellular factors, the mechanisms of myelination are not fully understood. Our preliminary work first showed that an membrane anchoring protein, Gab, regulated the myelination in CNS. Myelin-related proteins, such as MBP, MOG, MOBP, CNPase, were significantly reduced in Gab1/Gab2 conditioning knock-out mice. In this project, we continue to utilize molecular biology, biochemistry, immunochemistry and Cre-Loxp-based knock out mice to investigate the defects of myelination and OPC differentiation in the Gab1 and/or Gab2 conditioned knock-out mice and underlying mechanisms. We also investigate the action of Gab signaling in the injury of myelin and remyelination using the cuprizone-induced demyelination model.Our results may reveal the roles and mechanisms of Gab in myelination,OPC differentiation and remyelination in CNS and may supply a new therapeutic target and an animal model for myelin-related diseases and drug screening.

中枢神经系统的髓鞘由少突胶质细胞形成。髓鞘缺陷常见于多发性硬化症、白质损伤、精神分裂症等疾病中。形成髓鞘的少突胶质细胞由少突胶质细胞前体细胞（OPC）分化并进一步发育成熟产生。研究髓鞘发育和OPC细胞分化调控的机制对髓鞘相关疾病以及髓鞘损伤后的修复治疗具有重要意义。目前对髓鞘发育和OPC细胞分化的调控机制了解仍不完全。我们发现一类锚定蛋白Gab可能参与调节中枢神经系统髓鞘形成，在Gab条件性敲除小鼠脑中存在髓鞘相关蛋白表达的显著下调。本项目将在前期研究基础上，综合利用分子，生化和细胞生物学等实验技术研究Gab条件性敲除小鼠是否存在中枢神经系统髓鞘发育和OPC细胞分化缺陷及其可能的分子机制，并以此为基础利用小鼠脱髓鞘模型来研究Gab在髓鞘损伤修复中的作用。该项目将揭示Gab对中枢神经系统髓鞘发育，OPC细胞分化及髓鞘损伤修复的调控及其分子机制，为髓鞘相关疾病及新药的筛选鉴定提供潜在治疗靶点。

中枢神经系统的髓鞘由少突胶质细胞形成。髓鞘缺陷常见于多发性硬化症、白质损伤、精神分裂症等疾病中。形成髓鞘的少突胶质细胞由少突胶质细胞前体细胞（OPC）分化并进一步发育成熟产生。研究髓鞘发育和OPC 细胞分化调控的机制对髓鞘相关疾病以及髓鞘损伤后的修复治疗具有重要意义。目前对髓鞘发育和OPC 细胞.分化的调控机制了解仍不完全。我们发现一类锚定蛋白Gab1 可能参与调节中枢神经系统髓鞘形成，在Gab1 少突胶质细胞特异敲除小鼠脑中髓鞘相关蛋白表达显著下调，BG 组织化学、免疫染色与电镜观察也揭示Gab1 敲除造成髓鞘发育障碍。通过一系列体内外实验，本研究证实了Gab1 通过控制OPC 分化进而调控中枢神经系统髓鞘发育。在此过程中，Gab1 参与调节髓鞘基因的转录。而进一步的研究发现，Gab1 调节了多个髓鞘基因转录调节因子如Olig2，SOX10 等的表达或核表达，从而实现髓鞘基因的转录调节。同时，Gab1 敲除造成其下游GSK3β 信号失活，导致β -catenin 核转运增加，引起B-catenin 转录活性异常，这可能是Gab1 调节上述Olig2，SOX10 等转录因子表达与活性的分子机制。本研究详细阐明了与RTK 受体相关联的锚定蛋白Gab1 对中枢神经系统髓鞘发育的调控作用及可能机制，为髓鞘相关疾病及新药的筛选鉴定提供潜在的新治疗靶点和可靠的动物及细胞模型。