Role of DISC1 and NRG1 in oligodendrocyte development in schizophrenia

描述（由申请人提供）：精神分裂症（SZ）被描述为一种断开连接综合征，不同神经元，脑回路和脑区域之间的通信中断，导致适当/连贯信息处理失败。为了维持神经系统各级的功能加工和快速神经传递，神经元需要轴突有足够的髓鞘形成。髓鞘形成的成功取决于介导少突胶质前体细胞（OPC）募集、分化和迁移的外在和内在信号的协调相互作用。在之前的研究中，我们发现SZ的特征是多髓鞘和少突胶质细胞（OLG）相关基因和蛋白的表达显著降低。我们还发现，SZ中髓磷脂相关的表达缺陷与有丝分裂后OLGs中正常细胞周期阻滞的执行失败有关，这可能对髓磷脂功能产生不利影响。与SZ相关的染色体1q42上的基因组易位中断了精神分裂症-1基因（DISC1），可能产生截短和无功能的DISC1蛋白。我们最近对神经元特异性表达截断人DISC1 （DhDISC1）的转基因小鼠的研究发现，在发育和成年期间，OPC和OLGs以及细胞周期基因的标记物出现了强烈的失调，这表明DhDISC1可能对少胚胶质细胞前体的增殖和迁移、向OLGs的分化以及最终的OLG功能产生重要影响。本研究旨在深入了解SZ中OLG功能障碍的机制。这些目的包括：(1)评估非神经元DhDISC1对转基因小鼠神经胶质祖细胞迁移、增殖和分化的影响，确定DhDISC1表达靶向神经胶质祖细胞的发育群体；(2)通过研究DhDISC1介导OPC迁移、增殖和分化的通路（由NRG1、IGF1和Wnt引发）中关键效应子的基因/蛋白表达和磷酸化水平，研究可能介导DhDISC1影响OPC迁移、增殖和分化的分子通路；(3)在人死后大脑中检测连接功能缺陷DISC1与olg相关功能障碍的SZ蛋白的区域表达变化，并确定其与疾病的相关性。我们的方法是通过识别SZ中的神经生物学异常，使用转基因动物模型来揭示相关机制，并将动物模型的发现与人类大脑的实际结果进行验证，从而更好地了解SZ中OLG的发育和功能，并指导可能的预防或干预策略，从而直接影响公共卫生。

DESCRIPTION (provided by applicant): Schizophrenia (SZ) has been characterized as a disconnectivity syndrome where communication between different neurons, brain circuits and brain regions is disrupted leading to failures of appropriate/coherent information processing. In order to maintain functional processing and rapid neurotransmission at all levels of the nervous system, neurons require adequate myelination of their axons. The success of myelination depends on coordinated interplay of the extrinsic and intrinsic signals that mediate recruitment, differentiation and migration of oligodendrocyte precursor cells (OPC). In prior research, now replicated by many groups, we showed that SZ was characterized by significant reductions in the expression of multiple myelin and oligodendrocyte (OLG) associated genes and proteins. We also showed that the myelin related expression deficits in SZ are associated with the failure of execution of the normal cell-cycle arrest in postmitotic OLGs that may adversely affects myelin function. Genomic translocation on chromosome 1q42 associated with SZ that interrupts the disrupted-In-schizophrenia-1 gene (DISC1) may produce truncated and nonfunctional DISC1 protein. Our recent studies in transgenic mice with neuron exclusive expression of truncated human DISC1 (DhDISC1) have re- veal strong dysregulation of markers of OPC and OLGs along with cell cycle genes throughout development and adulthood suggesting that DhDISC1 can exert a major influence on proliferation and migration of oligoden drocyte precursors, their differentiation into OLGs and ultimately OLG function. The current proposal aims to gain deeper understanding into the mechanisms that contribute to the OLG dysfunction in SZ. These aims include: (1) assessing effects of neuron-exclusive DhDISC1 on migration, proliferation and differentiation of glial progenitor cells in transgenic mice and determining developmental population of glial progenitor cells targeted by DhDISC1 expression; (2) examining molecular pathways (elicited by NRG1, IGF1 and Wnt) that may mediate the effect of DhDISC1 on migration, proliferation and differentiation of OPC by studying gene/protein expression and phosphorylation of critical effectors of the pathways; (3) examining regional changes in expression of proteins connecting functionally defective DISC1 to OLG-related dysfunction in SZ in human postmortem brains and determine their disease relevance. Our approach is to understand better OLG development and function in SZ through an iterative process of identifying neurobiological abnormalities in SZ, using transgenic animal models to uncover the mechanisms responsible and validating the findings from animal models against real-world outcomes in the human brain and guide to possible preventive or interventional strategies with direct public health impact.