神经损伤诱导蛋白2（Ninj2）在髓鞘发育及损伤修复中的作用

Myelin sheath is an essential structure to maintain the proper physiological function of nervous system. Ninj2 (Ninjurin 2) is a cell surface adhesion protein, and its function in the central nervous system has not been reported. Ninj2 abundantly expresses in the oligodendrocytes, its expression peaks at immature oligodendrocytes, and decreases during oligodendrocyte maturation. In the oligodendrocyte lineages, despite its initial induction on proliferation of the oligodendrocyte precursor cells (OPCs), Ninj2 inhibits differentiation of OPCs. Moreover, Ninj2 induces cell apoptosis in the mature oligodendrocytes (mOLs), therefore significantly reduces cell number. RNA-seq analysis reveals that overexpression of Ninj2 affects oligodendrocytes proliferation and differentiation by its involvement in the regulation of mitotic cell cycle. And it also suggests that Ninj2 induces apoptosis of mOLs by upregulation of the genes involved in endoplasmic reticulum (ER) stress. In vivo experiments show that loss of Ninj2 gene in oligodendrocyte lineages promotes myelin development, as well as the remyelination process after LPC-induced demyelination. On this basis, we will perform further studies both in vitro and in vivo, to investigate the underpinning of the regulation on oligodendrocytes development by Ninj2. Further, we will attempt to explore the therapeutic potential of targeting Ninj2 and its related regulation pathways for demyelination diseases.

髓鞘是维持神经系统正常生理功能的重要组成部分。Ninj2 (Ninjurin 2) 是细胞表面粘附蛋白，其在中枢神经系统中的具体功能未见报道。实验发现，Ninj2在少突胶质细胞中大量表达。其表达水平在未成熟少突胶质细胞中较高，随细胞成熟而下降。在少突胶质细胞发育过程中，Ninj2诱导细胞增殖，抑制分化；同时Ninj2促进成熟少突胶质细胞凋亡。RNA-seq分析显示，Ninj2参与了细胞周期的调控而影响了细胞增殖与分化；并且上调内质网应激相关基因的表达而诱导细胞凋亡。动物实验显示在小鼠少突胶质细胞中特异性敲除Ninj2基因能够使髓鞘提前发育，并促进溶血卵磷脂（LPC）诱导髓鞘损伤后修复。在此基础上，我们将运用体内外实验系统，深入研究Ninj2影响少突胶质细胞发育的内在机制，分析其参与的信号通路，阐明其作用的分子机理，并探讨Ninj2及其作用相关的信号通路作为脱髓鞘疾病的治疗靶点的可能性。

抑郁症是目前最常见的一种心理疾病，影响着全球超过3亿人。近期的研究结果显示抑郁症的早期阶段往往伴随着髓鞘完整性异常，并随着疾病的进展而恶化。这些研究结果使得髓鞘及形成髓鞘的少突胶质细胞进入了人们的视野，其与抑郁症发生发展的相互联系也越来越受到重视。近年来，有研究发现在应激性抑郁症小鼠大脑皮层中，Ninj2表达水平显著低于健康小鼠，提示Ninj2的表达水平可能与抑郁症相关。本研究中，鉴于Ninj2主要在少突胶质细胞中表达，我们构建了少突胶质细胞特异性敲除Ninj2的小鼠品系，并从中观察到Ninj2基因缺失可使小鼠出现明显的抑郁样症状。在该小鼠品系中，Ninj2的缺失首先抑制了少突胶质细胞发育和髓鞘形成，伴随出现的是小鼠前额叶皮层及CA1区域内的锥体神经元形态与功能异常以及相应的抑郁样行为。在细胞实验中，我们发现少突胶质细胞中敲除Ninj2上调了细胞对TNFα的敏感性，激活由TNFα介导的细胞坏死程序，致使少突胶质细胞数量下降，髓鞘形成受阻。在细胞坏死过程中，趋化因子 2 (C-C Motif Chemokine Ligand 2, Ccl2) 的表达水平增加。Ccl2能够介导少突胶质细胞和神经元之间的相互作用。向体外培养的神经元中加入Ccl2能显著降低锥体神经元的活性。当使用药物阻断Ninj2缺失所引起的少突胶质细胞坏死过程后，Ccl2的水平下降，小鼠的髓鞘发育得到改善，而小鼠的抑郁样行为亦随之得以缓解。我们的研究成果阐述了Ninj2 调控抑郁症发生的生理机制，拓宽了少突胶质细胞在中枢神经系统中的生物学意义，同时也进一步丰富了少突胶质细胞与神经元之间的联系，并为临床研究中抑郁症的治疗提供了新的思路。