Molecular mechanisms of axon guidance and neural connectivity

轴突引导和神经连接的分子机制

基本信息

批准号：
7741327
负责人：
JONATHAN R TERMAN
金额：
$ 35.33万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/7741327
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 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 public health relevance ras GTPase-Activating Proteins ras Guanine Nucleotide Exchange Factors receptor relating to nervous system

项目摘要

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的互连。这些联系的形成或维持不当会导致神经异常，导致许多精神疾病和疾病。这些电路如何组装和集成？信号素是参与轴突连接形成和维持的最大蛋白质家族之一。信号素是在无脊椎动物和脊椎动物中发现的系统发育保守的分泌和跨膜蛋白。 Semaphorins利用丛集，这是一个在轴突表面发现的大型跨膜蛋白的家族，作为引导其作用的受体。丛蛋白实际上如何转导信号信号的理解很少，但对于学习词素雕刻和维护神经系统的重要性至关重要。那么，哪些策略将进一步定义这些重要机制，这些重要机制通过哪些词法和斑点直接神经连通性？在过去的二十年中，工作表明，轴突引导和连通性的分子机制在简单和复杂的动物之间得到了明显的保存。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。鉴于这种保护，我的研究计划的目的是关注苍蝇胚胎的简单神经系统中的一小组轴突，并表征将它们引导到目标的分子和机制。使用这种策略，我最近确定了一个新的细胞内蛋白质家族，这些家族对于指导Semaphorin/PlexIntiondented神经连接至关重要。在果蝇等简单生物中有一个微基因，而在包括人类在内的哺乳动物中发现了三个单独的麦克学基因，这些基因对于介导闪光蛋白和丛蛋白的作用也很重要。有趣的是，微蛋白包含多个已知与允许轴突生长，导航和形成连接所需的细胞骨架机械相互作用的区域。 micals还包含一个氧化还原酶结构域，词汇素轴突连接所需的完整性。该氧化还原酶结构域的存在与信号素介导的连通性中的首次氧化还原信号传导机制有关。该提案的重点的一个重要问题是确定摩尔旋转轴突的分子。对这个问题的最初见解是我们最近的鉴定，即Mical与神经元中含有蛋白质CAS的SH3域相互作用。 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剂，我们发现CAS和MICAL LING LINK丛集和整合素可介导轴突引导。我们的初步结果现在表明，CAS与G蛋白信号传导的特定介质相互作用，这表明Mical和Cas在调节轴突中的GTPase中起作用。我们将使用体内遗传和生化方法以及模型飞行轴突系统来测试以下假设：特定的GTPase及其调节剂是轴突导航的介体，并且在轴突指导过程中Semaphorins使用的细胞内信号传导机制中起重要作用。公共卫生相关性：我们的神经系统控制着出色的能力，例如将我们的思想投向纸张，只是因为我们的神经元在高度组织的网络中进行了通信。该建议的目的是更好地表征使神经元能够找到并相互联系的分子和机制。了解这些网络的组装，整合和维护的方式将暗示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，确定许多精神疾病的治疗策略，并在神经创伤后有助于健康的康复。