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: 8499937
• 负责人: PAVEL Leon KATSEL
• 金额: $ 30.32万
• 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/8499937
• 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（由申请人提供）：精神分裂症（SZ）的特征是一种断开连接综合征，其中不同神经元、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。为了在神经系统的所有水平维持功能处理和快速神经传递，神经元需要其轴突的足够髓鞘形成。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。在先前的研究中，现在被许多小组复制，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着减少。我们还发现，在SZ的髓鞘相关的表达缺陷与有丝分裂后OLG的正常细胞周期阻滞的执行失败，可能会对髓鞘功能产生不利影响。与SZ相关的染色体1 q42上的基因组易位中断了精神分裂症中的破坏基因（DISC 1），可能产生截短的和无功能的DISC 1蛋白。我们最近在神经元特异性表达截短的人DISC 1（DhDISC 1）的转基因小鼠中的研究已经揭示了OPC和OLG标记物沿着细胞周期基因在整个发育和成年期的强烈失调，这表明DhDISC 1可以对少突胶质细胞前体的增殖和迁移、它们向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SZ OLG功能障碍的机制。这些目标包括：（1）评估神经元排斥性DhDISC 1对转基因小鼠中神经胶质祖细胞的迁移、增殖和分化的影响，并确定DhDISC 1表达所靶向的神经胶质祖细胞的发育群体;（2）研究分子途径（由NRG 1、IGF 1和Wnt引起），其可能介导DhDISC 1对迁移的作用，通过研究基因/蛋白质表达和途径关键效应物的磷酸化来研究OPC的增殖和分化;（3）检查连接功能缺陷DISC 1与OLG的蛋白质表达的区域变化，SZ相关功能障碍，并确定其疾病相关性。 我们的方法是通过识别SZ中神经生物学异常的迭代过程，更好地了解SZ中OLG的发育和功能，使用转基因动物模型来揭示负责任的机制，并验证动物模型对人类大脑中真实世界结果的发现，并指导可能的预防或干预策略，直接影响公共卫生。