Molecular mechanisms of axon guidance and neural connectivity

轴突引导和神经连接的分子机制

• 批准号: 8257167
• 负责人: JONATHAN R TERMAN
• 金额: $ 34.97万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-20 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8257167
• 关键词: Actins; Animals; Axon; Behavior; Binding; Biochemical; Biochemical Genetics; Biological Models; Complex; Cues; Cytoskeleton; Development; Disease; Drosophila genus; Embryo; Emotions; Faculty; Family; GTP-Binding Proteins; GTPase-Activating Proteins; Genes; Genetic; Goals; Guanine Nucleotide Exchange Factors; Guanine Nucleotide-Releasing Factor 2; Guanosine Triphosphate Phosphohydrolases; Health; Human; Integral Membrane Protein; Integrins; Invertebrates; K-Series Research Career Programs; Learning; Ligands; Light; Link; Maintenance; Mammals; Mediating; Mediator of activation protein; Mental disorders; Modeling; Molecular; Monomeric GTP-Binding Proteins; Motor; Nervous system structure; Neuroglia; Neurologic; Neurons; Organism; Oxidation-Reduction; Oxidoreductase; Paper; Play; Positioning Attribute; Protein Family; Proteins; Psyche structure; Recovery; Research; Role; SH3 Domains; Semaphorins; Signal Pathway; Signal Transduction; Site-Directed Mutagenesis; Solutions; Specific qualifier value; Surface; System; Testing; Therapeutic; Thinking; Time; Trauma; United States National Institutes of Health; Vertebrates; Work; axon guidance; extracellular; fly; genetic regulatory protein; human BCAR1 protein; in vivo; insight; plexin; post-doctoral training; programs; ras GTPase-Activating Proteins; ras Guanine Nucleotide Exchange Factors; receptor; relating to nervous system

DESCRIPTION (provided by applicant): A normal functioning human nervous system requires the interconnection of billions of neurons. Improper formation or maintenance of these connections leads to neurological abnormalities that result in a number of mental diseases and disorders. How are these circuits assembled and integrated? The semaphorins are one of the largest protein families involved in the formation and maintenance of axonal connections. Semaphorins are phylogenetically conserved secreted and transmembrane proteins found in invertebrates and in vertebrates. Semaphorins utilize plexins, a family of large transmembrane proteins found on the axonal surface, as receptors to direct their effects. How plexins actually transduce semaphorin signals is poorly understood but is of importance for learning how semaphorins sculpt and maintain the nervous system. So what strategies will further define these important mechanisms by which semaphorins and plexins direct neural connectivity? Work over the past twenty years has revealed that the molecular mechanisms of axon guidance and connectivity are remarkably well-conserved between simple and complex animals. Simple animals like flies use many of the same axon guidance signals as mammals. In light of this conservation, the goal of my research program is to focus on a small group of axons within the simple nervous system of the fly embryo and characterize the molecules and mechanisms that guide them to their targets. Using this strategy, I recently identified a new family of intracellular proteins, the MICALs, that are critical for directing semaphorin/plexindependent neural connectivity. There is one MICAL gene in simple organisms like flies, while three separate MICAL genes are found in mammals including humans that are also important for mediating the effects of semaphorins and plexins. Interestingly, MICAL proteins contain several regions known to interact with the cytoskeletal machinery necessary for allowing axons to grow, navigate, and form their connections. MICALs also contain an oxidoreductase domain, the integrity of which is required for Semaphorin axonal connectivity. The presence of this oxidoreductase domain implicates for the first time oxidation-reduction signaling mechanisms in semaphorin-mediated connectivity. One important question that is the focus of this proposal is to identify the molecules through which MICAL steers an axon. Initial insight into this question has come with our recent identification that MICAL interacts with the SH3-domain containing protein Cas in neurons. Cas is a critical regulator of actin cytoskeletal dynamics in non-neuronal cells and we find that Cas and MICAL link Plexins and integrins to mediate axon guidance. Our preliminary results now reveal that Cas interacts with a specific mediator of G protein signaling suggesting the possibility that MICAL and Cas play a role in regulating GTPases in navigating axons. We will use in vivo genetic and biochemical approaches and the model fly axon system to test the hypothesis that specific GTPases and their regulators are mediators of axon navigation and play an important role in the intracellular signaling mechanisms utilized by semaphorins during axon guidance. PUBLIC HEALTH RELEVANCE: Our nervous systems control such remarkable abilities as putting our thoughts to paper only because our neurons communicate in highly organized networks. The goal of this proposal is to better characterize the molecules and mechanisms that enable neurons to find and connect with one another. Understanding how these networks are assembled, integrated, and maintained will suggest solutions to diminish the burden of mental illness, reveal fundamental mechanisms underlying thought, emotion, and behavior, identify therapeutic strategies for a number of mental disorders, and contribute to healthy recovery following neural trauma.

描述（由申请人提供）：正常运作的人类神经系统需要数十亿个神经元相互连接。这些连接的不适当形成或维持会导致神经异常，从而导致许多精神疾病和障碍。这些电路是如何组装和集成的？脑信号蛋白是参与轴突连接形成和维持的最大蛋白质家族之一。脑信号蛋白是在无脊椎动物和脊椎动物中发现的遗传上保守的分泌和跨膜蛋白。脑信号蛋白利用神经丛蛋白，一个在轴突表面发现的大跨膜蛋白家族，作为受体来指导它们的作用。丛蛋白实际上是如何传递信号蛋白信号的还不清楚，但对于了解信号蛋白如何塑造和维持神经系统很重要。那么，什么样的策略将进一步定义这些重要的机制，通过这些机制，信号蛋白和丛蛋白指导神经连接？过去20年的研究表明，轴突导向和连接的分子机制在简单和复杂动物之间非常保守。像苍蝇这样的简单动物使用许多与哺乳动物相同的轴突引导信号。鉴于这种保守性，我的研究计划的目标是专注于苍蝇胚胎简单神经系统内的一小群轴突，并描述引导它们到达目标的分子和机制。使用这种策略，我最近确定了一个新的细胞内蛋白质家族，MICALs，这是至关重要的指导semaphorin/plexindependent神经连接。在像苍蝇这样的简单生物体中有一个MICAL基因，而在包括人类在内的哺乳动物中发现了三个独立的MICAL基因，它们对介导信号蛋白和丛蛋白的作用也很重要。有趣的是，MICAL蛋白包含几个已知与细胞骨架机制相互作用的区域，这些机制是轴突生长、导航和形成连接所必需的。MICAL还含有氧化还原酶结构域，其完整性是脑信号蛋白轴突连接所需的。该氧化还原酶结构域的存在首次暗示了脑信号蛋白介导的连接中的氧化还原信号机制。这项计划的重点是确定MICAL引导轴突的分子。我们最近发现MICAL与神经元中含有SH 3结构域的蛋白Cas相互作用，从而对这个问题有了初步的了解。Cas是非神经元细胞中肌动蛋白细胞骨架动力学的关键调节因子，我们发现Cas和MICAL连接丛蛋白和整合素以介导轴突导向。我们的初步结果现在显示，Cas与G蛋白信号传导的特定介体相互作用，这表明MICAL和Cas在调节GTPases导航轴突中发挥作用的可能性。我们将使用在体内遗传和生化方法和模型飞轴突系统来测试的假设，即特定的GTP酶和它们的监管机构是轴突导航的介质，并发挥重要的作用，在轴突的指导semaphorins利用的细胞内信号传导机制。公共卫生相关性：我们的神经系统控制着把我们的想法写在纸上这样非凡的能力，只是因为我们的神经元在高度组织化的网络中交流。该提案的目标是更好地表征使神经元能够找到并相互连接的分子和机制。了解这些网络是如何组装，整合和维护的，将提出解决方案，以减轻精神疾病的负担，揭示思想，情感和行为的基本机制，确定一些精神障碍的治疗策略，并有助于神经创伤后的健康恢复。