精神分裂症相关DISC1选择性剪接导致少突胶质细胞分化障碍和精神行为异常

DISC1系精神分裂症高度易感基因，其选择性剪接异常，如DISC1-Δ3异常增加与精神分裂症发病密切相关，但机制不清。近年来研究显示，DISC1对少突胶质细胞（OL）的分化起负调控作用，而OL分化障碍与精神分裂症发病相关。我们的工作假设是：异常增多的DISC1剪接体通过对OL分化的调控，参与精神分裂症的发病。预实验结果已表明，过表达DISC1-Δ3可抑制OL分化，在此基础上，我们拟通过以下途径验证DISC1-Δ3参与精神分裂症的发病：（1）证明DISC1-Δ3可能与PDE4相互作用，干扰OL的分化；(2) 验证与精神分裂症相关的，lncRNA Gomafu减少可抑制OL内DISC1-Δ3的生成。（2）制备OL系特异性DISC1-Δ3过表达小鼠以模拟疾病状态，观察和分析动物行为学改变和对OL成熟分化特性的影响。该研究可望阐明DISC1选择性剪接异常调控OL分化，参与精神分裂症发病的作用机制。

Disrupted in schizophrenia 1 (DISC1) is a susceptible gene that highly related to schizophrenia and other psychiatry disorders. Recent evidence suggests that alternative splicing abnormality may result in an abnormal increase of splice variants, i.e. lacking exon 3 (DISC1-Δ3), which may contribute to schizophrenia pathogenesis with unknown mechanisms. Increased studies indicate DISC1 as a negative regulator for oligodendroglial differentiation and hampered oligodendroglial differentiation or dysfunction has been strongly linked to schizophrenia. We hypothesize that abnormal increased DISC1 spliced variants play an important role in pathogenesis of schizophrenia via regulating oligodendroglial differentiation. Our preliminary data show that over-expression of DISC1-Δ3 inhibits oligodendroglial differentiation. To investigate the contribution of DISC1-Δ3 for schizophrenia, we propose to examine: (1) DISC1-Δ3 interacts with PDE4 to inhibit oligodendroglial differentiation; (2) Down regulation of schizophrenia related IncRNA Gomafu inhibits DISC1-Δ3 expression within OLs; (3) Generate OL conditional DISC1-Δ3 overexpression mice to mimic disease condition, and test behavioral changes and OL maturation in the line. The completing of this proposal will demonstrate the mechanism underlying the role of the schizophrenia associated DISC1 splice variants on impairment of oligodendroglial differentiation and neuropsychiatric behavior. The results may also provide new insight into the pathogenesis of schizophrenia and related psychiatry disorders.