精神分裂症易感基因SOX11参与神经发育的分子机制

Schizophrenia is a complex genetic neuropsychiatric disorder afflicting approximately 1% of the general population worldwide. Accumulating evidence revealed neurodevelopmental disturbances in patients with schizophrenia. Genome-wide association study (GWAS) applied in the Chinese Han population indicated that the transcriptional factor SOX11 gene may be a susceptibility gene for schizophrenia. Previous studies have showed that SOX11 is involved in early-stage neurodevelopment and neuroplasticity. Therefore, SOX11 may induce emergence of schizophrenia by regulating neurodevelopmental signaling. In our previous work, we verified the association of SOX11 and schizophrenia in an independent case-control sample-set, and the results of in vitro cell experiments and in utero electroporation showed that SOX11 was involved in multiple phases of neurodevelopment, including neural proliferation and differentiation, neuronal maturation, neurite growth and neuronal migration. In this project, we will focus on three research directions: 1) observe the core events in neurodevelopment in the constructed Sox11 deficient mouse model; 2) investigate the transcriptional profile of SOX11 in neurodevelopment based on cDNA array analysis; 3) explore the related molecular mechanism of SOX11 regulation in neurodevelopment and neuroplasticity. This project will provide important information for revealing the pathogenesis of schizophrenia susceptibility gene SOX11 and the further study of schizophrenia etiology.

精神分裂症是多基因遗传的精神疾病，人群患病率约1%。越来越多证据显示精神分裂症患者存在神经发育障碍。中国汉族人群中进行的全基因组关联研究发现转录因子SOX11可能是精神分裂症易感基因，既往文献提示SOX11调控神经发育和神经可塑性。因此，我们认为SOX11基因可能通过调控下游神经发育通路影响精神分裂症的发病。本项目前期使用独立病例对照样本证实SOX11基因与精神分裂症关联，体外实验和小鼠子宫内穿孔结果显示SOX11参与神经发育多个阶段，包括神经干细胞增殖分化、神经突生长、神经元成熟和迁移。本项目将在三个方面进行研究：1)使用已构建的SOX11敲除小鼠模型观测其缺失后神经发育核心事件的改变；2)在已获得的表达谱芯片数据基础上，发现并验证神经发育过程中SOX11的下游基因；3)明确SOX11参与神经发育和神经可塑性的分子机制。本项目为揭示SOX11的致病机理和深入研究精神分裂症病因奠定基础。

精神分裂症是以患者基本个性改变，思维、情感和行为分裂，精神活动与环境不协调为主要特征的严重精神疾病，人群终生患病率约为1%。本研究前期采取精神分裂症候选基因策略，根据精神分裂症神经发育异常假说及大量尸检和科学研究报道，选择SOX11基因作为研究对象，在包含768例精神分裂症患者和1348例健康对照的中国汉族人群病例-对照样本中证实SOX11基因与精神分裂症显著关联，推测其是疾病的易感基因；同时，体外细胞实验和小鼠子宫内电穿孔结果显示SOX11参与神经发育多个阶段，包括神经干细胞增殖分化、神经突生长、神经元成熟和迁移。本项目执行期间重点阐明了：1）与精神分裂症关联的SOX11基因单核苷酸苷酸多态性对其自身表达具有调控功能；2）作为转录因子，SOX11基因调控众多参与神经发育的重要基因；3）SOX11基因对其下游两个重要神经发育基因SDF1和Reelin的转录调控机制；4）SOX11作为一个快速周转蛋白，其产生和降解间动态平衡，从而保证生物体成年后相对较少的蛋白库可以对周围信号改变具有较灵活的响应；5）SOX11基因敲除后影响小鼠神经迁移及神经板分层；6）SOX11基因参与脑缺血再灌注后的损伤修复以及神经可塑性。我们的研究揭示了精神分裂症易感基因SOX11的致病机理及其在神经发育阶段发挥的功能，为日后深入研究精神分裂症病因奠定基础。