Role of DISC1 and NRG1 in oligodendrocyte development in schizophrenia

DISC1 和 NRG1 在精神分裂症少突胶质细胞发育中的作用

• 批准号: 8641422
• 负责人: PAVEL Leon KATSEL
• 金额: $ 29.69万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8641422
• 关键词: 1q42; Address; Adult; Affect; Animal Model; Autopsy; Axon; Brain; Brain region; Bromodeoxyuridine; Cell Cycle; Cell Cycle Arrest; Cell Differentiation process; Chromosomes; Communication; DNA; Defect; Development; Disease; Failure; Flow Cytometry; Functional disorder; Gene Expression; Gene Proteins; Genes; Genetic; Genomics; Glial Differentiation; Human; IGF1 gene; Immigration; Intervention; Label; Lasers; Measures; Mediating; Mediator of activation protein; Molecular; Mus; Myelin; NRG1 gene; Nervous system structure; Neurobiology; Neuroglia; Neurons; Normal Cell; Oligodendroglia; Outcome; PDGFRA gene; Pathogenesis; Pathway interactions; Persons; Phosphorylation; Population; Predisposition; Prevention strategy; Process; Prosencephalon; Proteins; Public Health; Regulation; Research; Role; Schizophrenia; Series; Signal Pathway; Signal Transduction; Signaling Pathway Gene; Staging; Stem cells; Superior temporal gyrus; Syndrome; Testing; Time; Transgenic Animals; Transgenic Mice; analog; area striata; cdc Genes; cell motility; hindbrain; information processing; link protein; migration; mouse model; mutant; myelination; neurotransmission; novel; oligodendrocyte precursor; precursor cell; premature; progenitor; programs; protein expression; public health relevance; research study; success

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.

描述(申请人提供)：精神分裂症(SZ)的特征是不同神经元、大脑回路和大脑区域之间的通信中断，导致适当/连贯的信息处理失败。为了维持神经系统各个层次的功能处理和快速神经传递，神经元需要足够的轴突髓鞘。髓鞘形成的成功依赖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的特点是多髓鞘和少突胶质细胞(OLG)相关基因和蛋白的表达显著减少。我们还发现，SZ的髓鞘相关表达缺陷与有丝分裂后OLG的正常细胞周期停滞的执行失败有关，这可能会对髓鞘功能产生不利影响。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)，可能会产生截短的、无功能的DISC1蛋白。我们最近在神经元排斥表达截短人DISC1(DhDISC1)转基因小鼠中的研究发现，OPC和OLGs的标志物以及细胞周期基因在整个发育和成年期都发生了强烈的失调，这表明DhDISC1可以对寡核苷酸前体细胞的增殖和迁移、向OLG的分化以及最终的OLG功能产生重大影响。目前的建议旨在更深入地了解导致深圳OLG功能障碍的机制。这些目的包括：(1)评估神经元专属的DhDISC1对转基因小鼠神经胶质前体细胞迁移、增殖和分化的影响，并确定DhDISC1表达靶向的神经胶质前体细胞的发育群体；(2)通过研究DhDISC1对OPC迁移、增殖和分化关键效应因子的基因/蛋白表达和磷酸化情况，检测可能介导DhDISC1对OPC迁移、增殖和分化影响的分子通路(由NRG1、IGF1和Wnt诱导)；(3)检测死亡小鼠脑中连接功能缺陷DISC1和OLG相关功能障碍的蛋白质表达的区域性变化并确定它们与疾病的相关性。我们的方法是通过识别深圳地区神经生物学异常的迭代过程，使用转基因动物模型来揭示责任机制，并对照人类大脑中真实世界的结果验证动物模型的发现，并指导可能的预防或干预策略，从而更好地了解深圳的OLG发展和功能。